The Oncology Podcast

The Oncology Journal Club Podcast Episode 11: Practice Changers and Personal Insights from ESMO

• The Oncology Network presents The Oncology Journal Club Podcast • Season 2 • Episode 11

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As we head toward the end of the year, the Oncology Journal Club Podcast team reflect on learnings from the last big international conference of the year.

With 15 papers across various specialties, we've got you covered with an insightful exploration of all the pivotal studies. You can expect expert analysis alongside our unique blend of humour, banter and bad dad jokes.

With our incredible Hosts - Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson.

For papers, bios and other links visit the Show Notes on our website.

For the latest oncology news visit www.oncologynews.com.au.

We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.

The Oncology Podcast - An Australian Oncology Perspective

Speaker 1:

Welcome to the Oncology Journal Club podcast, a fun and educational oncology learning resource for medical professionals. I'm your producer, rachel Babin from the Oncology podcast. I'm joined by our esteemed hosts Professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. Today's episode is an ESMO digest. Cj gets us started with key upper and lower GI data, kate covers Pembro and HIV-associated Kaposi sarcoma, as well as neuroendocrine tumors and triple negative breast cancer, and Craig talks us through the GU and lung updates. There's so much analysis packed into the next 40 minutes and a few cringy dad jokes too, of course. For additional insights and links to the papers, visit the show notes on oncologynetworkcomau. The Oncology Journal Club podcast is produced with pride by the podcast team at the Oncology Network. Thanks for listening.

Speaker 2:

G'day Kia ora, kia ora. Welcome to episode 11 of the OJC Trans-Tasman version of the OJC podcast. Great to have you all listening in. We're getting some good feedback on recent episodes and increasing listenership, which is great news. Hello, dr Clark.

Speaker 3:

Hey Kia ora Craig, how are you?

Speaker 4:

Good and Professor Jackson how are you, kia ora? Pretty good. Thanks very much, craig. How about you? I heard you were not at an awards dinner last night. What's going on with that?

Speaker 2:

Oh, I was in Sydney so I didn't go. Yeah, so myself and Professor David Thomas won an award in the medical excellence section of an industry award, for I think it's about communication, and so I recorded a podcast interview with David last year about the Omico program and the Prospect program, which is enabling NextGen sequencing for all patients in Australia with advanced cancer and then plugging them into clinical trials. So we had a bit of fun doing the podcast and got this industry award.

Speaker 4:

So you're officially an award-winning podcaster. Well, it's great to have an award-winning podcaster on our team, it's true. I can be a bit of that and add that to our tagline yeah on our team. Sure, I can tell that.

Speaker 2:

And add that to our tagline. Yeah, and a shout out to our extensive listenership. Obviously worked recently, Chris, because we just sort of segued into mentioning that you were running for the UICC and you were elected to the board, is it or?

Speaker 4:

committee, yeah, yeah, the board of directors. So thanks very much to all the listeners who got their organisations to vote for me. So the UICC, as many people know, is the political membership body for cancer policy and global oncology and every member organisation gets to vote for their 16 directors. And so I went to Geneva and I campaigned on being a pretty good third choice. I told people I didn't want to vote for someone else as their first choice because there's a lot of people better than me. Actually, there's an awful lot of people who are taking better than me, but I'm actually not bad. I'm probably third. So if I were to be third, I'd have C-shirt made up which said Chris Jackson pretty good third choice, with a big picture of a Kiwi went around OGC podcast on the board.

Speaker 2:

Fantastic and first ever Kiwi elected.

Speaker 4:

First ever Kiwi based Yep, sencha Aranda was a present of UICC. Now not many people know that Sencha was actually born in Winton, which is in New Zealand, but Australia claims Sencha as their own these days and she was based in Australia when she got that.

Speaker 2:

So first, you hear her name, we know that, we know she's got that accent, that accent Australian accent.

Speaker 4:

Anyway, let's get to the data. Let's get to the data.

Speaker 2:

So we're going to focus a little bit on the ESMO meeting. There's been a lot of post-ESMO meetings held in Australia, presumably in New Zealand as well, some interesting data. So we're just going to sort of look at some of the top line. Maybe some of the practice changes from that meeting.

Speaker 2:

Chris, I went to the meeting and I must say it's getting so big. There was something like 30,000 attendees. It was really interesting. You know you can get ribbon envy when you see people walking around with the ribbons on their badges, but I noticed that a really tiny proportion of people are ESMO members and it's so expensive to attend. Now I was thinking they really should give a really substantial discount to the members because it's so expensive to attend. Now I was thinking they really should give a really substantial discount to the members because it's a big money-spinning thing and a lot of industry people. And one of the things that disappoints me about the meeting is they have industry-only forums over lunch so there's nothing else on and you kind of you know, if you want to go to a session, you kind of have to go to an industry session. So it's an interesting meeting got so big.

Speaker 2:

I think it needs to maybe go like ASCO and just unfortunately have it in the same city every year. That's accessible, with flights, accommodation, and it's not plonked way out of town somewhere which the conference center in Barcelona is. To come from towns nearly 45 minutes or an hour by public transport. So it's always fun going, but it's a big money and time commitment and then when you get there, the sessions are full and then the overflow rooms are full and everyone's sitting in the corridor on their laptops watching the presentations on their laptops, which you could do in the comfort and safety of your own home. So it's good fun to go, but it's not all a bed of roses at these meetings. I think they've got almost too big.

Speaker 4:

Yeah, well, and I think that the conferences certainly have to add a point of difference. I mean, the online experience these days is so good, so if you just want the data, you get it better online than you do in person. So it's still that networking which is really important. And part of that networking is what happens in the evenings, isn't it? That's right, and also having people around you where you can actually sit and discuss the data in more detail. I think people from Australia and New Zealand just have a real sense of how far away these bases are, because it's, you know, day and a half to get there, most of the time recovery in totally different time zones. It's a challenge, so I tend to go to one a year. Really, I haven't been to ESMA for a long time because it is a very long way away.

Speaker 3:

I think, though, chris, to the other issue perhaps, is these European cities aren't set up to house 30,000 people within walking distance. Yeah, unlike Chicago, which really is. When you and I were in Vienna many years ago, we were miles away from the conference.

Speaker 4:

Yeah, that may have been an accommodation expense choice. Barcelona is one of my favorite cities. I love the tapas, I love the beaches, I love the temperature. In July, when World GI Congress is on, it's a lovely, lovely, lovely place.

Speaker 2:

Yeah, and it was great catching up with some people, and that's one of the things, I guess, for regional people as well. We maybe don't see our colleagues face-to-face as much, so it was great catching up.

Speaker 4:

No, that's right. I'm really pleased to see as well, Craig, that you're very careful with your suntan, because you're still, you know, with your sun cream. You're still there.

Speaker 2:

All right, let's get into it. I think, Professor Jackson, are you going to go first and tell us what you thought of some of the highlights.

Speaker 4:

Yeah, I was going to cover off the GI stuff today. First of all, what a surprise, I'm a one-trick pony. No, I'm two-trick. I do upper and lower GI. There you go.

Speaker 4:

The Podium 303 study, or Interact 2, was presented at ESMO this year. Podium 303, maybe they named it optovacitly to get themselves on the podium, but this was in patients with previously untreated locally advanced or metastatic squamous cell carcinoma of the anal canal. And this built on the Interact study, which defined carboplatin and paclitaxel as the preferred chemotherapy backbone in anal squamous cell carcinoma and understanding that as an HPV-driven cancer, the TMB is often quite high and so there is a potential role for a new therapy. Previously we had data for second-line therapy with immune therapy in anal cancer and this is the first time it's been combined in a randomized study. So this study randomized 308 patients, so it's the largest ever anal cancer study to either carbotex or placebo, or carbotex or let me see if I can get this right retifanlamib Now, that is not people who are fans of our health minister, shane Ritchie, but retifanlamib, Hans. You can call in and tell us that I've got it wrong. Is that a Kiwi dad joke? Yes, and Ritofanilamab, I should say, is the Insight PD-1 monoclonal antibody. So it's PD-1 inhibitor.

Speaker 4:

Primary endpoint was progression-free survival, which was met with the median PFS going from 7.4 months to 9.3, which is a grand total of 1.9 month. Extension Hazard ratio was a tasty 0.63. When you look at the PFS curves it's good to see the PFS curve is flattening at around about 12 months, which is suggesting that with longer follow-up maybe we'll start to see that plateau that you see in other cancers. But I think that's a little early to see and there's no early crossover of the curves as there is in PD-1 monotherapy studies.

Speaker 4:

Os is immature but promising and currently the readout on OS is plus six months. This may be a situation whereby the OS is better than the PFS by some order of magnitude. There are other studies in particular going on with modified DCF, with atezolizumab going on which is a single-arm phase 2. We should see some more randomized studies. But I think this pretty much is the high watermark in metastatic anal squamous cell carcinoma and most people will consider carbotaxel with a PD-1 inhibitor now the standard of care. So I think that's an important study. Small gain in PFS, not OS reported yet, but I think people are going to accept it.

Speaker 3:

I feel like my rebuttal I could just put on play. You know, I could just push a button and go you're combining two agents versus not combining those agents. Is this current-current versus sequential? Have we got any evidence? Blah, blah, blah. So I feel very much like you know same thing different day. It's really hard to sell when people are self-funding drugs to say, you know, at this point, yeah, it's, it's tricky, but the problem is, of course, every human doesn't get another suck of the sad, for a less crude expression.

Speaker 4:

You know they only get one chance and some people will be willing to pay that yeah, I agree with that, um, kate, and I also think that is why we need to have the os data available, so we can really help people understand that if it's going to help them live longer and not just control the tumor on a scan. Uh, for, and that's why OS is such an important endpoint. And I agree with you, around the crossover as early as late, and that's why you need the paper to see what the crossover was and see how many people had it. And that's a situation where people should have had access to crossover because we know it's active in the second line. Well, to cover, yeah, the Top Gear study.

Speaker 4:

This was an AGITG study which had been going on for many years. We recruited some patients to this. This is in gastric cancer. Now, this was conceived in the era where perioperative chemotherapy was a standard and people debated the role of post-operative chemoradiotherapy. So that was the McDonald study surgery first, followed by chemorad and then perioperative ECF. They were the two standard treatments at the time when Top Gear was conceived, they could see the CRITIC study that was looking at post-op chemo, rt following on from the urgent chemotherapy, and so AGITG looked at pre-op chemo, radiotherapy and ECF versus ECF chemo. It was later modified to include FLOT and to cut a very long story short. Unfortunately it was an absolutely and utterly plum negative study OS curves you can't even get a credit card between so that negative.

Speaker 4:

The secondary endpoints of PCR were better for chemoradiotherapy, which just reinforces Kate. This is where I push my replay button. Isn't PCR a rubbish endpoint when you're looking at comparing chemorads versus chemotherapy? And it doesn't translate into necessarily overall survival. So chasing PCR is not necessarily the end point that we think it is, certainly in ones where you have a high rate of systemic relapse. So that was a shame. A lot of people in Australasia put a lot of effort into that study. Trevor has been a servant of the Australasian GI community running that study for so long. It'd be heartbreaking for the investigators but of course actually heartbreaking for the field not to have it advanced as well.

Speaker 2:

Yeah, it was, but it's important, I think, an important negative study practice changing because there's still a lot of centres in Australia that are giving this approach and now I think people will switch to the perioperative flight chemotherapy for fit patients. This study was published in the New England Journal, which is, you know, we've often disparaged it as a positive results. But this negative study was published in the New England Journal, which is, you know, we've often disparaged it as a journal of positive results. But this negative study was published in the New England and because it will change practice, I think, and in resource-constrained times and resource-constrained countries not pointing any fingers, you know and in regional areas where people sometimes have to travel and displace for weeks on end to receive these treatments, it's good to know that the treatment's not needed. So kudos to Trevor and all of the people at the AGI-TG and all of the investigators, patients and their families who are recruited to this important study.

Speaker 4:

Yeah, you look at a study in a different way when you see some of those numbers on the Kaplan-Meyer curve underneath it and you know that they're patients you enrolled. Eh, you look at a study in a very different way when you see it like that.

Speaker 2:

That's exactly right.

Speaker 4:

Keynote 811 was also reported. Now Keynote 811, it's another of the Keynote Checkmate bunch of numbers studies. This was for HER2 positive gastric adenocarcinoma. Now HER2 positive gastric adenocarcinoma, metastatic disease, the standard of care is chemotherapy with trastuzumab since the days of the TOGA study where certainly IHC3 plus patients got a five-month boost in overall survival and so that has been the standard everywhere. It just became the standard in New Zealand this year Kate's trying to suppress her laugh Just become the standard of care in New Zealand. Now it's generic.

Speaker 4:

Anyway, this is an important question because Keno811 randomized patients receive standard of care chemo with trastuzumab to either that chemo with either pembrolizumab or placebo. Now this actually reported early with response rate and when it reported early with response rate the response rate was more than 50% with the four combination with the quad with the pembrolizumab included and a lot of people jumped at that time and moved straight to chemotherapy trastuzumab, pembrolizumab and I certainly had a lot of patients ask me about it. They pushed it. Anyway, the final overall survival results have come back and there's an improvement in OS of 3.2 months with a hazard ratio of 0.8, so a very minor proportional benefit 3.2 months there in overall survival.

Speaker 4:

The curves separated mildly. There doesn't seem to be any suggestion, looking at those curves, of any particular subgroup. Who's going to benefit? T's out and the PFS is a measly 1.9 months. So OS of 3.2 months is at the lower end of the ESMO magnitude of benefit scale. The hazard ratio of 0.8 is at the lower end of the ESMO magnitude of benefit scale. But it's important to note that the chemotransfusamab arm performed well at 16.8 months compared to, say, 15 months, which you might have expected from historic data. So it did okay. So I think again that'll be adopted because people will take any OS game, but it's a small step forward.

Speaker 2:

Fantastic.

Speaker 4:

Yeah, other ones to cover off Zolbituximab. How did you?

Speaker 1:

say that.

Speaker 4:

Zolbituximab, zolbituximab, and there was a bit of hype about this. This is the spotlight study. I prepared this when it came out a couple of weeks ago. Craig, I'm looking at my notes.

Speaker 2:

They're now quite this is the anti-chloridin 18.2. There's quite a number of those in development, I understand, but this was one of the first presented studies. Zolbituximat. We'll have that rolling off our tongues.

Speaker 4:

We will, indeed 2018.2 has only been a target for two or three years. This has come through the development pipeline really quickly, hasn't it? As a biomarker, as a single-arm phase two. And now we've got PFS analysis from Spotlight and Glow. 1,072 patients are randomized to Zolbutuximab or the placebo group, so a very, very large study. In the combined analysis, the median PFS was 9.2 months in the Zolbutuximab group and 8.2 in the placebo group, as a ratio 0.71.

Speaker 2:

Is this called a filibuster?

Speaker 4:

Mediate overall survival 13.7 versus 16.4 months. Hazard ratio 0.77. So again a modest increment there, a modest increment. I will show you the PFS curves if this was a video podcast. Again a modest advance there. And there's a flattening of the Zolpidoximab curve in PFS. But these are very small numbers so it'll mature a wee bit more.

Speaker 2:

So, chris, the target, the anticlaudin 18.2,. Do you know off the top of your head how many people with gastric cancer or GOJ cancers overexpress the anti-Chloridin 18.2. And this was an enriched population, for that Is that correct.

Speaker 4:

That's correct. They had to be 18.2 expressors, so I did present this at the ESCO podcast a couple of years ago.

Speaker 2:

Yeah, I reckon it's about 30%, is that right? It's 20 to 30. It's quite a reasonable number, but it's not the majority.

Speaker 4:

So Chlorine, 18.2, was more frequently observed in early gastric cancer 30.2%. So yeah, it's about 20 to 30%. It's different according to geographic location as well, so particularly high in Europe and Middle East. So there's geographic variation as well. So I'm sure we'll see that done according to molecular subtypes in time to come all right, and you're telling us about pons gromab, speaking of tongue twister, new products you have to work on the captions to their names, aren't they um? Ponzi gromab, ponzi gromab, ponzi, ponzi gromab ponzi, ponzi, gromab, someone.

Speaker 2:

It's going to be called ponzi, isn't it? Or? Or Ponzi, ponzi.

Speaker 4:

Cancer. Cohexia is a really big problem, right, you know? I think anyone who's worked in the clinic will know how big a problem cancer cohexia is. It's meaningful to patients associated with sarcopenia, associated with reduced activity, increased fatigue and the like. Cohexia is strictly defined as a 5% loss of weight in the last six months, which, with a strict definition that's probably stricter than I would use. We tend to use 10% weight loss, but that is the strict definition of 5% or 2% weight loss if your BMI is less than 20. So if you're already at a low point, it's only a very small change in weight.

Speaker 4:

Previous studies have shown that the level of growth differentiation factor 15, gdf15, which is a cytokine, has increased in Ghex here. So this particular therapy is a monoclonal antibody targeted against that cytokine. It was a randomized placebo-controlled study with four arms. One is placebo and the other three are increasing doses of ponzogramab, ponzogramab, ponzogramab, and the main finding was that with the highest dose of ponzograbab, ponzograbab and the main finding was that with the highest dose of ponzograbab, the weight gain over 12 weeks was up by 3 kgs. So is that meaningful? Well, it could go up by 3 kgs if you're retaining fluid.

Speaker 4:

So you have to look at other things like muscle mass and functional outcomes. Well, anorexia symptoms were improved and electronic activity monitoring, ie, fitbit, was also improved as well. So patient functional outcomes and anorexia symptoms improved also. So I think we can expect to hear more about this drug. We're going to hear more about the duration of therapy and we'll be hearing more about muscle base. There are some concerns with the study. It wasn't corrected for multiple testing. When it's a forearm study, that does reduce its power. There's limited racial diversity in the population as well, so there are other problems. They use Bayesian analysis for that as well, which I don't understand well enough to offer them for Fair enough. So those were the ESMO highlights from me and, of course, team New Zealand doing very well in Barcelona at the moment.

Speaker 2:

Fantastic Quick question. The Ponsigrimab that's a Mab, so presumably it's a monoclonal antibody and is it an IV treatment given with their other systemic therapy?

Speaker 4:

I can't tell you off the top of my head if it was IV or subcut, but it was given every four weeks for three doses for a total duration of 12 weeks.

Speaker 2:

Great, okay, no doubt it'll be expensive. And, kate, we've talked before about other… Olanzapine Olanzapine, which is pretty cheap.

Speaker 3:

Very cheap. Yeah, 2.5 milligrams BD throw it around, great stuff.

Speaker 4:

Oh, you bet he not wants a day Kate.

Speaker 3:

Yeah, throw it into my little ankylotic cancer lovies, yep and Creon. Please think about Creon 100% Creon and Olanzapine. Yes.

Speaker 2:

So this, to get a listing in Australia, would have to be very efficacious and very much cheaper compared to the comparator, which presumably perhaps would be olanzapine. So it'll be interesting to see, going forward, what happens with this drug. So look, all of those studies you mentioned, Chris, just for the listeners, they can click on the links click-o-de-su. They're all being concurrently published in the New England Journal of Medicine and so we've put the links in the notes. Were you going to mention the 10-year data for ipinivo?

Speaker 4:

No, because I've not reviewed it.

Speaker 2:

Okay. So there was some interesting data presented, 10-year follow-up from the original epinevo studies in melanoma showing long-term survivors, I think of about 35% 40%, which is interesting and clear plateau on the curve.

Speaker 3:

I would love to hear what a brand-new oncologist maybe somebody who started training after these things were invented. They're like oh yeah, you give immunotherapy to melanoma. Some people do, well, yeah that's right. Because we remember everybody dying.

Speaker 4:

Yeah, yeah, yeah. The DCIC era, you know, and interferon and the like. It was a pretty desperate time affecting young people in such a devastating way.

Speaker 2:

Yeah it was. I remember so many you know patients you looked after young, including one of my best mate's brothers who was a dynamic young lawyer in his late 30s who you know died reasonably quickly, and so the landscape is completely different and we just hope that that, you know, this is a first generation, our checkpoint inhibitors. Can we push those plateaus up? That's the hope, isn't it, Kate? I know you're going to tell us about breast cancer, but I think you've got a couple of other interesting things. You've got a NET paper and a Kaposi's sarcoma, again currently published in the New England Journal.

Speaker 3:

Well, I have to tell a confession that actually I think the Kaposi's paper was first presented at ESMO 2023, but it has recently been. The full paper's recently been published. So this is from Fred Hutchinson, the Fred Hutchinson Dr Lorraine Cancer Indian Therapy Trial number 12, pembrolizumab in HIV-associated Kaposi's sarcoma. So for those of you who don't treat Kaposi's that's HIV-related, the first thing you do is treat the HIV. Many of the Kapos disappear. A young woman of mine, for example, went from an albumin of 10 to being completely well as soon as she reconstituted her immune system. Interestingly, maybe because of the population of HIV-positive patients in the States, they use only cisgender men. Anyway, these gentlemen all got 200 milligrams of pembrolizumab Q3 weekly with a response rate overall of 62% and 88% of the first line Progression-free survival of 28 months and duration of response not reached.

Speaker 2:

So 200 milligrams of pembrolizumab.

Speaker 3:

Of pembrolizumab yeah, Gives you these stonking response rates. Gives you these stonking response rates. Interestingly, that is a similar response rate that you see in PACLI, but a much longer duration of response. So interesting, and also perhaps puts paid to the fact that many HIV-positive patients are excluded from immuno-oncology trials and 25% of patients did end up with toxicity that required steroids but no grade fives.

Speaker 2:

So, in the context of modern HIV treatment, how many patients now actually go on to develop Kaposi's that need treatment?

Speaker 3:

Because if we're getting much better at actually controlling the HIV, which you mentioned was the first step, so I have been back in my current role for more than 10 years and we have seen three patients and we look after a community of six 700,000 with a big refugee population. And without identifying these people, the vast majority had for some reason not had access to HIV therapy.

Speaker 2:

Yeah, okay, fantastic.

Speaker 3:

Right. My second one is a neuroendocrine tumor one, and after telling Dr Jackson off Professor Jackson off about presenting progression-free survival data without OHS data, I'm going to do the same thing. So this is heavily pretreated patients with NETs.

Speaker 3:

So this is heavily pre-treated patients with nets, and they separately recruited and reported pancreatic and extra pancreatic nets, yep, and they gave them capazantinib at a 60 milligram dose which if you've given it is quite stonking. Uh versus placebo, uh. And in the pancreatic lot, pfs went from four months to 14 months with only an overall response rate of 20%. But that's what that disease does. And in the extra pancreatic progression, free from four months to eight and a half months, most patients were grade one or two, a couple of threes in there, 65% had grade three toxicity or greater. And just in case you're interested, their previous treatments 95% stomatostatin analogs, 60% PRT, 80% everolimus and, depending on whether they're pancreas or extra pancreas, 60% or 30% temozolomib, with or without cake. So you know, quite heavily appreciated. So that's another option, fantastic.

Speaker 3:

And then my final one, something we've talked about a lot Keynote 522, schmidt et al from Barts in London finding the overall survival data and the absolute difference of adding cabralizumab to neoadjuvant chemotherapy in an unselected population of typical breast cancer patients is 5% and it's real. Interestingly, of course, this is a study with a co-primary endpoint of PCR and in those patients who'd had a PCR, the overall survival difference between the two groups so regardless of how you got there was less than 1% and not statistically significant In those patients that didn't get to a PCR. Regardless of how they got there, if you were in the PEMBRO arm you had a 6% better survival than those that didn't have early PEMBRO, so maybe it suggests there's a benefit beyond achieving PCR. I think this segues quite nicely into the paper that Craig's been reading.

Speaker 2:

Yeah, it was just. You know, I noticed that you put in the chat that you were thinking of presenting this and then I found came through this morning on one of those table of content feeds paper from the Journal of Oncology Practice, some real-world data published in the current edition, so I'll put the link to that. It's called Real World Immune-Related Adverse Events in Patients with Early Triple Negative Breast Cancer who Received Pembrolizumab. So it's a retrospective study from a community hospital patients who received PEMBRO with chemo between 2021 and 2023, excluding those enrolled in clinical trials, and so there was an ethnically diverse population. In the US, 34% of patients had immune-related adverse events, commonly the endocrinopathies and GI. There were about 10% of patients ended up being hospitalized, mostly because of colitis, and two patients died. So basically 1% of this population died from the toxicity of the Pembro. And so that just contextualizes that 5% absolute benefit and I think most patients, especially younger population, would jump at the 5%. But obviously in the consent process this kind of data helps contextualize the risk-benefit.

Speaker 4:

I think that's right, craig, and I think when I'm dealing with patients who are having IO4 melanoma for example, certainly in the adjuvant setting, I talk about a 5% likelihood of life-altering side effects. We've had some patients who have been really really harmed by immune therapy in terms of neuropathies or pneumothadies or myopathies or whatever. You can get quite a lot of debilitating conditions. Patients who've had type 1 diabetes develop as a result. It's about 5%, I think, of proper life-changing side effects and I think that has to be contextualised when you're looking at these quite small benefits as well. So I think you need to really counsel people about the long-term harms and of course, people naturally will emphasise the importance of disease control and perhaps think less about long-term side effects in the short term, which is why it's important to have that really meaningful conversation about what those long-term toxicities look like so.

Speaker 2:

in this paper, 20% of people ended up with an endocrinopathy, so they would have stayed on thyroxine or steroids or other agents.

Speaker 3:

This is a younger female cohort and it worries me that you know that isn't being taken into account and I do hope and I do congratulate, that real-world data will continue to be and real-world long-term data will continue to be collected, because the vast majority of these women are going to be cured with or without epimbrolizumab and, just like paclitaxel and oxaloplatin, have lifelong toxicities for some patients that are miserable. I think we need to take that into account.

Speaker 2:

I always say to patients, if we had a crystal ball it would be easy. And so the message to me is, as a community of researchers, we need to have better biomarkers that might predict toxicity and better predictive factors. You know that tailor the treatment population so that we actually target those most in need and minimize the risk to those who don't need it. So you know it's still early days in the whole field and I would hope that in the years ahead we get better at being able to tease out an individual patient and help them in that decision-making process.

Speaker 3:

I think a couple of things. So I think we need to stop talking about treatment minimization and start talking about right sizing, because if I were an unwell person, I don't want my treatment minimized. I want my treatment right sized.

Speaker 4:

I think we should start calling Goldilocks zone treatment really.

Speaker 3:

Just right. But the other thing I had to deal about that's cute. Craig, you say crystal ball. This is where maybe we're edging a generation here. The difference is, I always say PlayStation. I say if we could do this 100 times we'd find the right strategy.

Speaker 2:

But we don't get to do it 100 times. I don't understand that. Yeah, I didn't get that. So yeah, all right, we've got a couple more to finish off.

Speaker 2:

Firstly, in GU there was a landmark paper in bladder cancer, so perioperative doverlimab with neoadjuvant chemotherapy in operable bladder cancer. So this was presented by Thomas Powell at ESMO. This was a large phase three study, one-to-one randomization between cisplatin-based chemotherapy with doverlimab given both before treatment followed by a further eight cycles afterwards, and it showed the first of the primary endpoints was events-free survival with overall survival as a key secondary endpoint. But they did have some overall survival data to show and so that estimated event-free survival at 24 months was 67% in the Davilumab group, 59.8% in the chemo alone group and the overall survival at two years was 82 months in the dovolumab group versus 75%. Interestingly, the grade 3, 4 toxicity showed no difference which I found hard to work out, and the treatment-related adverse events leading to death was 0.6%.

Speaker 2:

More patients who got the dovolumab were able to have a radical cystectomy compared to the comparison group. So that was the Niagara study and you know that was the discussion thought this was practice changing treatment, concurrent New England Journal publication. In absolute terms there was clear survival advantage hazard ratios of 0.75. So at two years overall survival, 82 versus 75. So 7% benefit and 0.6% risk of death.

Speaker 4:

So, craig, given it was a Niagara study, did they have waterfall plots?

Speaker 2:

Oh, I thought you were going down the Viagra pathway because this was a GU cancer.

Speaker 3:

Oh, I thought someone was going to mention flooding too.

Speaker 4:

It's a little bit too soon for that cake. They've just been underwater. So, craig, can I just ask you a question in terms of advanced urothelial cancers, is there any difference in advanced cancers between the PD-L1s versus the PD-1 agents? So is this the optimal agent to be used in the preoperative strategy, or do you think that PD-1 inhibitors are any different?

Speaker 2:

I don't think there's ever any data to argue that. Chris, there was a talk at ESMO about not all checkpoint inhibitors are the same, but I think the message that we're getting seeing in a lot of cancers, with people with locally advanced disease, it's the perioperative approach rather than the adjuvant approach that is important. So giving doses, you know, we've seen it in gastric cancer, We've seen it in non-small cell lung cancer, We've seen it now in bladder cancer, we see it in melanoma. So giving some doses, presumably when the immune system's intact, hasn't been damaged by surgery which is immunosuppressive chemotherapy alone, and lymph node's intact, that approach seems to be more efficacious than giving some doses afterwards. And the right sizing might be limiting the number of doses, tailoring it. We've got evidence in melanoma. People have had a complete response with the pre-op doses. You don't need the post-op, etc. So maybe that's where we'll get to in these tumors.

Speaker 4:

That's right. I mean ensuring that the patient's got the maximum number of neoantigens for the agent to observe and also, as you are alluding to as well, having the TILs around tumor-referred lymphocytes around in the adjacent nodes and amplifying those really as well. So you've cut those out which you can then actually maximize too. So I think you're right. The pre-op strategy with having some tumor load does appear to be an important concept.

Speaker 2:

Yeah. And then, speaking of duvelumab, I'm going to talk now about a study in limited stage small cell lung cancer, again considered to be potentially practice-changing study. This is called the Adriatic study. So we saw Pacific in the non-small cell lung cancer population, patients receiving dovolumab after chemoradiotherapy. This is Adriatic in the limited stage small cell. So patients without progression after concurrent chemoradiotherapy given a year of dovolumab and again it showed significant difference in overall survival regardless of whether they'd received PCI or not, which is interesting. So postulate there is that maybe by giving the adjuvant immunotherapy you may not require prophylactic cranial radiation, or that would be the subject of more debate and analysis. So in this study the median overall survival in the attempt to treat population was 55 months versus 33 months, or at three years it's 56 versus 47% hazard ratio 0.73. So clear separation of the curves, especially as time went on. This is the interim analysis, so we'll need further follow-up but it may be that this becomes it was called immediate practice changing in the discussion.

Speaker 4:

Yeah, well, I mean chemotherapy, preoperative chemotherapy, sort of preoperative chemotherapy in bladder cancer adds what? 8% to overall survival compared to surgery alone. So that's a standard and this is adding 8% further. So I guess the case for this is just as strong as the case for an adjuvant chemotherapy.

Speaker 2:

And I'll just mention a couple of other things, a couple of new targets in the targeted therapy session. So MTAP deletions, which occur in 15% of cancers. There's a new active agent called AMG193. It reintroduced the concept of synthetic lethality. So we saw that concept emerge with PARP inhibitors where patients have lost one homologous repair mechanism gene and so if you knock out the other one with a PARP inhibitor you have an effect on the tumor cells but relative sparing of normal tissue. And so the same concept is emerged in these MTAP deletions with this agent which creates synthetic lethality in patients that have a MTAP deletion with a small but clearly active response rate in non-small cell lung cancer, pancreatic cancer and biliary tract cancers.

Speaker 2:

And then the other target just to mention is KRAS G12D. We see a lot of those mutations in patients if they do get their tumors tested with next-generation sequencing. So it occurs in about one in eight colon cancers and one in three pancreatic cancers. And so this was a selective protein degrader called ASP3082, with clearly inactive drug. And so we await further clinical studies. But just highlighted to me that you know through our knowledge of mutations that there may be more precision medicine treatments in the not too many years ahead.

Speaker 4:

Yeah, that's exciting. I mean G12D. When you take K-res mutations, they're great ones to be able to target, aren't they?

Speaker 2:

Yeah, that's right.

Speaker 4:

Tricky one in colorectal.

Speaker 2:

And obviously pancreas would be great if you had a target there, wouldn't it exactly? And so, uh, then I'll just mention one other significant thing. So that was esmo. Um, I will mention something outside of the world of esmo, if I may, and that's, uh, the fda issued a guidance on decentralized clinical trials, or dcts. So they they'd issued some interim guidance during the COVID lockdown period, and then this is their final guidance, really encouraging the use of telehealth in the conduct of clinical trials with the aim of improving recruitment and improving access to disadvantaged populations, either geographically or otherwise disadvantaged populations. So, trial-less listening.

Speaker 2:

I'd urge you to have a quick look at this guidance. It's an easy read. It encourages, for example, using telehealth visits for screening patients, for consenting patients, for visits in between doses of treatment and then working with local providers in a networked way to deliver drug, using a risk-based analysis of what's appropriate to treat, to deliver remotely. They encourage the upfront design of studies considering the telehealth elements and they encourage co-design with consumers to answer that question about what's acceptable to deliver remotely and with local providers. They give some guidance on if someone's delivering care but doesn't need to have an in-depth knowledge of the investigational brochure or the investigational product, they don't need to be listed as an investigator.

Speaker 2:

So the big difference between DCTs and the Australasian Tally trial model is in Australia we encourage that delivery remotely and that who's doing what is documented on the supervision plan, which is like a site delegation log but across sites. So interesting guidance and just to blow the old trumpet, the iron trumpet, oh, we're going high tech. So there's no expense spared in the production. So Elizabeth Wilson, who certainly many of the Australian trialists would know, works with IQVIA, australian New Zealanders, which is one of the largest CROs in the world. Myself and Sabe Suberson in Townsville wrote a letter to the editor to the Lancet Oncology pointing out the importance and potential significance of this enabling model of care, and that's been published in Lancet Oncology.

Speaker 4:

Well, fantastic, great coup.

Speaker 3:

Congratulations. Thank you, ho mai te paki paki.

Speaker 2:

Oh, that's. Whatever that means.

Speaker 3:

Swing on the clapping yeah.

Speaker 2:

So it's been a real cook's tour through a whole lot of wide-ranging papers there, but I think a significant number of those may well influence practice, especially in the first world. We'll wait and see, but yeah, always great to review some of the hot data from the big conferences. And how are your?

Speaker 4:

Qantas pyjamas, Craig. How are they on the fly? They're great.

Speaker 2:

I've restored my stock of them. My wife wants me to throw out the old ones, but you know, with all the COVID lack of travel, they've been wearing out. So now I've got a couple of pairs of new Qantas pyjamas, which are fantastic. I'm wearing them as we speak.

Speaker 4:

The audience really needed that day.

Speaker 3:

We're so lucky there's no video.

Speaker 4:

The audience is just going wild with that. I'm going to ask ChatGPT to come up with a picture of Craig Underhill. That's our favourite.

Speaker 2:

On that note we might say goodbye, Thanks very much. Thank you for our listeners. If you're enjoying the podcast, please spread the word. Thanks, Rachel for the production. My pleasure for our listeners. If you're enjoying the podcast, please spread the word. Thanks, Rachel for the production.

Speaker 1:

My pleasure.

Speaker 2:

Thanks everybody, and we'll see you all in a few weeks, or we'll listen to you all in a few weeks.

Speaker 3:

Bye for now.

Speaker 1:

Thank you for tuning in to the Oncology Journal Club podcast, proudly brought to you by the Oncology Podcast. Part of the Oncology Network For healthcare professionals. Seeking regular news, updates and insightful discussions, we invite you to join our community at oncologynetworkcomau. Your free registration includes a complimentary subscription to our weekly publication, the 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 Babin signing off for the Oncology Journal Club podcast.