The Oncology Podcast

Episode 5: Prostate Cancer Treatment + Alcohol + Adjuvant Pembro + Quick Bites

• The Oncology Network • Season 2 • Episode 5

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Join us on this episode of The Oncology Journal Club Podcast as we dissect the latest research that point to new standards of care.

Join our esteemed Hosts, Professor Craig Underhill, Dr. Kate Clarke and Professor Christopher Jackson for the low down on the latest oncology papers.

Craig looks at how three-agent regimens have revolutionised the treatment of metastatic hormone-sensitive prostate cancer.  Kate asks how alcohol affects lethal prostate cancer risk.  And CJ explores the promising results of adjuvant pembrolizumab in resected renal cell carcinoma with his typical in-depth, high-speed and highly nuanced analysis.

Then we shift gears to our popular Quick Bites section (and yes, CJ is at the crackers again!). We look at the halted KeyVibe Adjuvant Melanoma Study, a Chinese trial on oesophageal squamous cell carcinoma, a small trial on dual tyrosine kinase inhibitors for BRAF mutant stage 3 melanoma, the TOPAS1 trial on divalimab in advanced biliary tract cancer and rural clinical trial enrolment. 

As always, The OJC team provide a robust analysis of the latest findings in oncology research. Tune in for a comprehensive, insightful and entertaining review of cutting-edge oncology developments.

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

Rachael Babin:

What is the best approach to the new paradigm of metastatic hormone-sensitive prostate cancer treatment combinations? Is adjuvant PEMBRO associated with a significant improvement in overall survival in patients with clear cell renal cell carcinoma? And have you ever wondered if a drink or two might affect healthcare professionals' risk of lethal prostate cancer? Kate professes expertise until Craig comes along with an intriguing gap in the analysis. Welcome to the Oncology Journal Club podcast, your go-to source for in-depth discussions on the latest oncology research, tailored for medical professionals. I'm your producer, rachel Barron from the Oncology Podcast. I'm joined by our esteemed hosts Professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. For additional insights, links and comprehensive bios of our hosts, visit the show notes on oncologynetworkcomau, produced with pride by the podcast team at the Oncology Network. We invite you to join us as we delve into the intricacies of oncology research and its clinical implications.

Craig Underhill:

G'day. Kia Ora, kia Ora, so Kia Ora. Kate, how are you going over there on the other side of the ditch?

Kate Clarke:

Very well.

Craig Underhill:

It's a shame we don't have visuals people because she just took a swig of wine. It's the evening, very well.

Kate Clarke:

It's the evening in New Zealand. We're always a couple of hours, if not decades, ahead of you over there on the other side of the ditch.

Craig Underhill:

Hardly. Kia ora Chris.

Christopher 'CJ' Jackson:

Kia ora. Craig, today I'm coming to you not from across the ditch, but I'm from across the wall. From Dr Clark I've heard the pleasure of visiting Wellington today, so Kate and I are recording in adjacent rooms. So if you're too mean, we'll just gang up on you.

Craig Underhill:

Yes, I did notice that article in the chat. About what was it? Wine bars of Wellington. So look out Wellington. The oncologists are in town and it's of relevance to one of our papers in today's episode. So we're up to episode five. It's amazing, so I think starting to hit our strides. We had some really great feedback with episode four. People said it was fun. I use the adjective chaotic as well, but it's definitely fun and information packed. So who's leading off today with their long paper?

Christopher 'CJ' Jackson:

I think that's you, Craig. It's you, Craig.

Craig Underhill:

Oh, that's right, I think it's me. So I picked a paper from one of our favorite journals, jama Oncology. This is a clinical review and education called Metastatic Hormone Sensitive Prostate Cancer and Combination Treatment Outcomes a review. So the people who treat prostate cancer will probably be fully across the detail in this review. But I thought, given the general audience that we have, it would be important to mention this review. And this is really a new paradigm of care that we're in with metastatic hormone sensitive prostate cancer, in which we use three agents rather than two as the standard of care. So this paper goes back and reviews a number of phase three randomized clinical trials conducted over the last 15 years or so, and the first set of those were comparing the new androgen receptor inhibitors with ADT. And then we moved into the paradigm of comparing the combination of ADT, docetaxel plus or minus an androgen receptor inhibitor, and so that's become the standard of care in the field.

Craig Underhill:

So all of these trials use some new definitions of high risk and high volume disease that came about in the development of these trials. So high volume or high burden disease is defined as visceral metastases and or four or more bone mets, and at least one of those is outside of the vertebral column or pelvis, and so that's been used in about eight of those randomized trials to stratify patients. And then the concept of high risk disease, which is at least two of Gleason score, eight or more, three or more bone mets and the presence of visceral metastases, and three of the later studies utilize that as well to stratify patients algorithm, suggested management algorithm based on whether patients have high volume, high burden disease or high risk disease, which is used increasingly in clinical practice. The three main studies are Enzomet, and there were some sites for that in Australia, peace One and Arison. So Enzomet looked at the role of enzalutamide and included as the standard of care ADT plus docetaxel for ZygCycles, plus a non-steroidal angiozine receptor inhibitor such as biclutamide. Piece one was a randomization between abiraterone, adt and docetaxel versus ADT, docetaxel, zygcycles and Aracins was the same design but using darolutamide, and so each of those studies showed significant progression-free survival and overall survival, statistically significant but I think clinically meaningful as well, and so in the setting now metastatic hormone sensitive prostate cancer, the standard of care has really become those three agents, so ADT, docetaxel and one of the new androgen receptor inhibitors.

Craig Underhill:

So the authors of this paper come up with an algorithm. Firstly, they suggest assessing frailty, remembering that a lot of these patients are over 70. And this is probably the first time I've seen this in a contemporary review. But they actually suggest using the G8 screening tool to look at the patient's risk. So if they're fit, they recommend then active treatment. If they're vulnerable, they suggest a discussion of active treatment versus supportive care and there's actually some ongoing studies looking at that question in that population. And if they're frail to really look at supportive care rather than active treatment, it's quite a sensible approach.

Craig Underhill:

Then for those considering active treatment, they've got metastatic disease. At diagnosis you look at the disease burden and the risk score. So patients who have metastatic disease de novo or those with high volume, high risk disease, then the standard of care should be consideration of the three agents. And so if you want to follow the results of the trials, that's a choice between abiraterone and darolutamide plus the docetaxel. For those who have recurrent disease or low volume, low risk disease. They tend to do better and that's really a discussion between the ADT plus androgen receptor inhibitor or the same combination plus the docetaxel. So what's missing is some trials that compare those two approaches. So the authors suggest that they are reasonable choices in that lower risk population.

Craig Underhill:

Then the choice of the agent really comes down to a consideration of side effects. So abiraterone can cause some problems with hypotension. It needs to be taken with a steroid and it's an activator of enzymes, so there's some drug interaction. The same with enzalutamide. Enzalutamide crosses the blood-brain barrier and there's reports of cognitive change in some patients. But darolutamide doesn't cross the blood-brain barrier and may offer some advantages in the side effect profile.

Craig Underhill:

So in my own practice and of course the darolutamide has not been available for very long, so I don't think anyone who wasn't involved in the clinical trials has an extensive experience. But in the experience to date is that darolutamide does seem to be better tolerated and doesn't need to be given with steroid. So anyway, as I said, interesting paper. I think we're in a new paradigm where we're increasingly using these three drugs upfront for the younger and fitter patients, and I'll see what Kate thinks. I know Chris is going to ask about cost, probably, but these drugs have been listed by the PBAC in Australia, so that's on the basis of cost effectiveness. So presumably it is a costly intervention for society, but it's been shown to be cost effective to get a listing.

Kate Clarke:

Chris, remind me I don't treat prostate cancer In prostate cancer in New Zealand. We can't use abiraterone this early, can we?

Christopher 'CJ' Jackson:

So you can use abiraterone first line or you can use it second line. There's criteria around that I understand, but I've given up prostate cancer for a couple of years so I'm not super on top of the criteria for it. The questions around abiraterone in New Zealand, where you can't get access to it, include things like do you have it in a full stomach, therefore you can use a lower dose or do you source it from America where you can get cheaper access to it? And certainly many patients are importing abiraterone who can't otherwise get it. So I think the cost element is relevant to people in jurisdictions where it's not funded. Certainly, indolutamide is a heck of a lot more expensive than abiraterone internationally, and I have no idea what derolutamide costs either. Craig, can I ask you a couple of questions? Certainly, most of these trials were done before PSMA PET scanning. Are most people getting PSMA PET scanning these days, and do you just consider PSMA PET, the same as all other staging investigations still use the same criteria?

Craig Underhill:

A lot of patients are getting PSMA PETs. So, chris, they're probably being upstaged. But I think these trials were based on CTs and bone scans. But I would have to go back and check the detail of the studies. It's a good question. There's my homework for next episode.

Christopher 'CJ' Jackson:

Next question yeah, Also, I noticed that doubling time isn't a feature in those criteria for considering aggressive diseases PSA doubling time less than three months is that out of fashion now?

Craig Underhill:

It's used in the non-metastatic carcinoid-resistant prostate cancer, which is a rare subgroup where men are failing the ADT, the PSA is going up, so we use the doubling time to determine whether they are eligible for darolutamide.

Christopher 'CJ' Jackson:

And how do you interpret those patients who've got, say, tiny, tiny, tiny but scattered rib mets, for example, as opposed to one great big, huge, hulking sacral alar met, which is only one by definition, but heck, it's a whole.

Craig Underhill:

Well, it comes down to that high volume, high risk use, chris. But if men are presenting with metastatic disease, they tend to do badly anyway, compared to the men who have been treated for early prostate cancer and then relapse. So you take all that into consideration in the individual patient.

Christopher 'CJ' Jackson:

Good stuff. Intensive treatment sounds like it's the way to go for those high risk patients.

Craig Underhill:

Yeah, I think so. I think that seems to generally become the standard of care. Okay, interestingly, you've put forward a prostate cancer paper to discuss today.

Kate Clarke:

Yeah, it would be fair to say I'm an expert in one of the words in my title. So the paper that I wanted to present it's epidemiology, and my colleague, dr Brendan Louis would say that there are the stats, damn stats in epidemiology. Lies, damn lies in epidemiology. So this is alcohol intake and the risk of lethal prostate cancer in the Health Professionals Follow-Up Study. So the Health Professionals Follow-Up Study was a biennial survey of health professionals which remember that that will be relevant for something Craig wants to interject later. Curiously, although there doesn't appear to be a benefit, a difference in the outcomes of those men who did not have prostate cancer at the beginning of the survey, those that did were less or had had prostate cancer, were less likely to develop lethal prostate cancer if they drank particularly red wine. And I had not. Being an expert in prostate cancer or men, despite being a straight married woman, I had thought this was reasonably well controlled. But Craig tells me that I've missed one essential factor.

Craig Underhill:

Yeah, I looked through it. They did a multivariate analysis to control for a whole lot of other variables, but I'm aware at least of one study I think there's several that showed that ejaculation reduces your risk of prostate cancer. So cleaning out the pipes seems to reduce the risk of prostate cancer. So I see that that wasn't a variable, and so my theory, my hypothesis, would be that if you drink a couple of glasses of wine in the evening, you might get a little bit more motivated and might increase the libido and therefore increased chance of intercourse or ejaculation and reduce your risk of prostate cancer. How's that for an hypothesis? You heard it here first on the OJC.

Christopher 'CJ' Jackson:

You can also keep drinking, craig, and drink so much. Get hypogonadal, drop your testosterone levels and that would also protect you against prostate cancer.

Craig Underhill:

Yeah, that's right, but it was talking about mild intake, I think right.

Kate Clarke:

Yeah, three glasses, a max of three glasses a day. I have an alternative explanation. This is a health worker's study and you know I've worked in hospitals for 25 years and there's a hell of a lot of wankers in hospitals, and so I suspect that they think they're controlled for that already. Rach is like. I'm going to edit that out.

Christopher 'CJ' Jackson:

Well, so I'm drinking red wine for my prostate cancer health, kate, what's your excuse?

Kate Clarke:

Much like I have a sexually transmitted accent. I suspect that maybe there's some sexually transmitted alcohol intake I'm doing my husband a favor.

Craig Underhill:

So is that the other variable? So alcohol intake by the partner, is that associated with reduced risk or not?

Kate Clarke:

Well, there you go, there's your PhD, Craig.

Craig Underhill:

So, Kate, I think for your homework for the next episode will be to present a paper review of all the cancers that are associated with three glasses of wine a day. It's an increased risk, of which there, I think, is considerable number?

Kate Clarke:

I'm very relieved, Craig. That was your question.

Craig Underhill:

I genuinely thought you were going to send me the ejaculation papers as my homework oh, you could if you'd like, but okay, no, I don't think this would be a reason for people to suddenly take up three glasses of alcohol a day. But a very interesting paper, interesting discussion. I'm glad we could skirt around that as much as we could.

Christopher 'CJ' Jackson:

You're relieved, Kate. I thought Craig was relieved.

Craig Underhill:

I'm not touching that. Chris, would you like to present your?

Christopher 'CJ' Jackson:

and the OJC gets reported to..

Craig Underhill:

So, Chris, what fascinating long paper have you got for us today? Hopefully something other than prostate cancer.

Christopher 'CJ' Jackson:

I'm going very highbrow today, Craig, but we're sticking with the GU theme. This is adjuvant pembrolizumab and resected renal cell carcinoma. This is the overall survival result. So we've had the DFS results for adjuvant pembro and RCC out for a while but now we've got the OS data and of course in an adjuvant study OS is king or queen or president, if you're not a monarchist. So the context of this, of course, is that there have been several trials of active agents in advanced disease which have been trialed in early stage disease which have impacted on DFS but haven't impacted on OS. So the adjuvant sunitinib study was negative. Checkmate 914, which was ipinevo an adjuvant, was negative and Emotion 010 with atezolizumab was negative as well for overall survival. So several negative studies so far, so a great deal of interest in this one as a randomized phase three where patients were randomized one-to-one to receive either pembrolizumab 200 mg flat dosing every three weeks for a year versus placebo, so placebo-controlled, not an arm which prolonged DFS, actually versus placebo. There were almost 500 in each arm, so it was a big study and patients were randomized to receive treatment within 12 weeks. They had to be E coli 0-1, had to have completely resected M0 disease or resected oligometastatic M1, not brain mets. They had to be T3 or T2 with grade 4 or sarcomatoid features. So high risk, intermediate to high risk. Primary endpoint of the study was DFS, but this was adjuvant. So OS is important and this is the overall survival data update published in the New England Journal of Medicine, so of course it's positive. Yeah, it has to be, it's in the New England Journal. So the outcomes were 55 deaths in the placebo arm and 86 in the placebo arm, with a four-year overall survival of 86% in the placebo versus 91% in the Pembro the hazard ratio of 0.62, which is lower than the previous report which had an OS of hazard ratio of 0.52.

Christopher 'CJ' Jackson:

Looking at the subgroups, interestingly for DFS sorry for OS, I should say males did better than females on adjuvant immunotherapy and that's seen in a number of immune therapy studies where the men do better than women. Women don't get the same benefit from IO in many contexts as men do, so that's interesting. And those with ECOG0 did better than those with ECOG1. No other subgroups showed any particular predelictation or favorability, including those sarcomatoid ones. In the DFS there was no difference between male and female but, reiterating, there was a survival difference between male and female, favoring one, and those who had resected M1 disease did better than those who had M0.

Christopher 'CJ' Jackson:

One of the important points in adjuvant studies is looking at a post-progression crossover in studies where you're investigating an active agent. So where you know that Pembrolizumab works in advanced disease and it improves PFS, dfs, os in the metastatic setting, you're really arguing should you use it early or should you use it late. So you have to see high post-protocol therapy for PD-1 inhibitors. I'm going to talk about that in a few minutes. When you look at the therapy on relapse, 80% of those in PEMBRO and 85% of those in placebo arm who relapse got subsequent therapy and 70% of the placebo arm who relapse got PD-1. Again, I'm going to break that number down a little bit more in a minute. In terms of toxicity, 21% of those on PEMBRO discontinued due to adverse events and the profile was pretty similar to other IO arms. I think that's relevant though for an adjuvant study. We'll talk about that in a moment. If you put it through the ESMO calculator, looking at magnitude of clinical benefit, this would score an ESMO A. That's the highest ranking that ESMO can give it, based on a hazard ratio of 0.65 or less for overall survival. So that's the top ranking.

Christopher 'CJ' Jackson:

This study has been criticized by some notable international luminaries, including Ian Tannock, who criticized the post-protocol therapy, and he also noted that there was potentially some informative censoring which potentially favoured the investigational arm. Tannock noted that more patients in the preembolism of the arm were censored and if you recalculated it to a point whereby, where those patients were censored, if you counted that as a progression event, then the significance went away. The hazard ratio was 0.8 as opposed to 0.62, but it attenuated. So when you censor patients, you take them out of the analysis, but if there's a difference in the censoring between arms, that could be called informative censoring, which means it changes the interpretation of one arm and therefore that has to be considered. And when you look at the adjuvant NEVO study or ipinevo study, there was no difference in censoring between the investigational arm and the placebo arm. So that informative censoring was criticized by Tannik and group.

Christopher 'CJ' Jackson:

The other thing we need to talk about is a 5% overall survival gain in the context of an adjuvant immune therapy where 85% plus of people are cured. Now, anyone who listens to this podcast probably will have used IO in the past and will know that IO is a really, really, really good treatment until it's not. And I think we've all had patients who suffered from life-altering toxicity in terms of encephalopathy, in terms of disabling myopathies, in terms of disabling neuropathies. Endocrinopathies are usually much more manageable with therapies, but people can be really debilitated by long-term IO toxicity and we're recognizing more and more lactox. So we have to weigh up that 5% OS gain against genuine morbidity long-term in an otherwise cured group.

Christopher 'CJ' Jackson:

Let's also break down that post-protocol therapy arm a little bit more 210 people relapsed in the placebo arm.

Christopher 'CJ' Jackson:

172 got any therapy, 145 got drug therapy, 101 got PD-1 therapy. So when you calculate the proportion who got post-protocol therapy, what's your numerator, what's your denominator? 101 getting PD-1 therapy Is the denominator 145 who got drug therapy, therefore meaning 70% of people got post-protocol therapy, or is it 101 out of the 210 who relapsed and that's 50% of post-protocol therapy getting PEMBRO? So when you start to look at it in terms of what's your numerator and what's your denominator, it might not be quite as rosy as they're suggesting at 70%. So I think we have to think about that in a bit more detail. Nonetheless, I think this is going to be practice changing for many people around the world. So I think people who've got T3RCC or T2 with sarcomatoid features or resected M1 disease and are going to get referred to medical oncology. Medical oncology is going to be discussing a year's worth of adjuvant Pembro with people and you're going to be treating an entire population, 85% of whom will never need treatment, for that 5% overall survival gain and that's the paper.

Craig Underhill:

Yeah, so it's interesting, Chris. I went back to look at some of the toxicity and you couldn't actually find tables about toxicity in the paper. I think they've gone into the appendices, yeah. yeah, so there's 20% of people came off treatment because of a serious adverse event, but it's hard to see the detail of how many of those, as you described, this life-changing toxicity. But the 5% benefit historically is not as substantial and if you have a discussion with the patient, many will accept that. Kate does breast cancer 5% in breast cancer adjuvant studies is a reasonable benefit, right, most patients will probably take that, but they're often younger population. But, kate, what's your thoughts on the magnitude of the benefit there?

Kate Clarke:

I think this is really interesting and I think there is perhaps a need for more patient-informed. What is a meaningful difference? I think Chris and probably Craig did too recruited to Scott, which was a subset of IDEA back in the day, and it had a second randomization which I've never seen the outcomes for. So they asked people at zero whether they were happy to have three months versus six months of chemotherapy, and then some patients were randomized at three months to whether they wanted three months or six months and then they asked them their preferences. So the people who had been randomized at zero months and the people who have been randomized at three months and people who have been exposed to therapy make different decisions and I think a one in 20 benefit means 19 and 20 are not, and we don't really need to see the tables.

Kate Clarke:

There's nothing magical about these patients. One in 20 will have something awful that requires them to go to hospital and may kill them if they're not looked after properly. Two in 20 are going to have lifelong supportive medications. This is not a non-toxic regimen. You're right. In breast cancer people are happy in some jurisdictions New Zealand women, probably a little bit more pragmatic to accept a 1% benefit and so Oncotype DX outcomes. They are validated at a funny threshold, but I think it depends how you sell it to a patient. So if you say I've got something that can improve your chance of being alive by X percent, people will say yes. If you say I've got a drug that is going to be completely pointless for 19 out of 20 people, very few people will take it, and that's the salesperson in us. So I think there's more place to be informed by what patients actually value and where their risk-benefit ratio is.

Christopher 'CJ' Jackson:

Yeah, I think that's right, Kate. A couple of things around that In particular. The grade 3, 4 tox was 18.6% with IO rather than 1.2% and 5%. We wouldn't treat many people with stage 2 colon cancer in New Zealand for that benefit, but, like you say, they wouldn't in the breast cancer world. So patient values are really critical here and I also think in a therapy where most people are cured anyway, you know that marginal gain at the end you're exposing a lot of people to tox war, but patient-centered decision-making is king there.

Craig Underhill:

And Chris, you mentioned that ESMO magnitude of benefit scale. We've covered that before in the Oncology Journal Club podcast a few years ago. Rachel's on the call doing all the work in the background, Rachel. I think it'd be great for us to put a link to those papers in today's notes because if people, especially trainees, if they're not aware of that paper, it's worth having a look at that to understand that. I think it's a really useful scale.

Rachael Babin:

Before we delve deeper into today's episode, we want to thank you for your continued support. If you're a healthcare professional who shares our passion for these insightful discussions, we invite you to join our community at oncologynetworkcomau. Registration is free and includes a complimentary subscription to our weekly publication, the Oncology Newsletter, and regular podcast updates. But that's not all. Your voice matters to us. We value your input and welcome your feedback and paper recommendations. Together, we can shape the conversation and drive the direction of future episodes. Visit oncologynetworkcomau today and join us in our mission to advance the field of oncology through collaboration, knowledge sharing and innovation.

Craig Underhill:

All right, who wants to go first with their quick bites? Chris?

Christopher 'CJ' Jackson:

All right, first quick bite.

Craig Underhill:

Those playing along at home. He's just taken a bite of his cracker, a swig of his red wine. Prostate cancer preventing red wine. You wash that down and push on Chris.

Christopher 'CJ' Jackson:

That's our musical introduction to the quick bite section, as Jackson chomping on a cracker and news just out the Key Vibe Adjuvant Melanoma Study looking at pembrolizumab versus pembrolizumab with a TIGIT inhibitor, which is another immune checkpoint, versus pembrolizumab with a TIGIT inhibitor, which is another immune checkpoint. An investigational agent was a drug called Vibostolamab, which sounds like a mixer drink that many first-year university students would have, has just been halted due to futility. So this is a study that was recruiting widely throughout Australia and New Zealand and at the first interim analysis the IDMC shut the study down because there was no gain in relapse-free survival and there was an indication that people were discontinuing earlier because of excess toxicity. So this is another adjuvant melanoma study which unfortunately has failed and seems to have failed because of excess toxicity causing discontinuation. So the AEs on the adjuvant arm are pretty critical in the study here too. Yeah, good on you, chris.

Craig Underhill:

I think it's important that we present negative studies.

Christopher 'CJ' Jackson:

So what else do you have? Yeah well, this is a Chinese study looking at squamous cell carcinoma of the esophagus, people getting definitive chemoradiation with either cisplatin, 5-fu or capsidobin and oxaliplatin. Herskovich chemoradiation has remained king for those who are unable to go to definitive therapy, even though people are recommending a variety of different regimes including Folfox or carboplatin with paclitaxel, with high-dose radiotherapy. We don't have many randomized comparisons. This Chinese study was of squamous cell carcinoma only, so no adenos at all in it. T1bn positive or T2 node any age, 18 to 75, e coli 0.2, randomized 1 to 1 to 1 to capcitabine monotherapy, xalox or cisplatin with 5-EFU. Primary endpoints were two-year overall survival and basically the PFS and overall survival curves were pretty similar. In those three arms, those who received consolidation therapy after the primary chemoradiation seemed to do a wee bit better, which was encouraging because I think many of us aren't certain about whether those two cycles of consolidation chemotherapy after chemorads are worth doing. But those arms did seem broadly similar. That's important for a number of reasons. For starters, a lot of people with squamous cell carcinoma of the esophagus have reasons why they can't have cisplatin, including renal failure, and the data for oxaliplatin and squamous esophageal carcinoma is actually quite weak. So it's good to have a study which is looking at oxaliplatin as a chemoradiation agent in squamous cell carcinoma.

Christopher 'CJ' Jackson:

Editor's comment said that single agent was of course better tolerated with comparable overall survival. Noted that the limitations were a small sample size, not non-inferiority designed. And said, somewhat tellingly, it's uncertain how this is applicable to a global population, which always gets on my heckles a wee bit, because when you do an adjuvant study like the Pembroke and RCC and it's done in the US and Europe population, the editors don't say we wonder how this is applicable to a global population. So I think we have to be careful about being condescending towards Asian studies. The data is the data. It's been done well and it's useful additional data.

Craig Underhill:

I agree, chris, and when I had a look at it this afternoon before we recorded, my first impression was again was this just underpowered sort of 70, 80 patients on each arm to really give us the answer? But anyway, as you say, it's not common to see the randomized data. I understand there's an interesting presentation at ASCO coming up, which is with the cross protocol versus chemotherapy, which is a preoperative, isn't it? Preoperative, postoperative study?

Christopher 'CJ' Jackson:

That's quite right. That's the adenocarcinomas, yeah, and GOJs and that's going to be exciting. That's in the plenary. But OJC will be doing a very special ASCO edition and we'll be covering it.

Craig Underhill:

Great. Thank you, Kate. Would you like to do your quick bites?

Kate Clarke:

Of course my quick bites are very quick. One is a very small trial, but I think it makes a point about using dual tyrosine kinase inhibitors in BRAF, mutant stage 3 melanoma, neoadjuvant and adjuvant. It's kind of a sandwich and they have stratified their results by PCR, which sadly there is no difference Really, if you get a PCR or not, you don't do any better. And I think the important which is not true with immunotherapy and not true in other diseases using chemotherapy. So just as two points.

Kate Clarke:

Firstly, I'm just not sure tyrosine kinase inhibitors are a good curative. You know we keep seeing this. They're great at deferring relapse. I don't think they cure very many people. And the second point is that when we are using surrogate endpoints, we have to make sure that surrogate endpoint is validated in the population in which we are using it. So that was my first that we are using it. So that was my first. That was just me being very lectury.

Kate Clarke:

And then my second point is heartbreaking. So the Divalimab plus gemcitabine and cisplatin in advanced biliary tract cancer TOPAS1, a trial, frustrating in that it doesn't report the MMR standards of the patients who are getting Divalimab. But this is the quality of life data and I quote, there is no detriment to gaining the three agents over the second agents and therefore this is a tolerable regimen. I'm sorry, that's just doublespeak, and I think if you're providing palliative chemotherapy to somebody, you've got to be doing it with a quality of life improvement rather than a lack of deficit. So I just found that paper concerning. It worries me sometimes that maybe we've lost our way.

Craig Underhill:

Lucky you weren't reviewer too, Kate.

Kate Clarke:

I think I'm getting so old and so grumpy that very few things would get published if they went past my desk.

Craig Underhill:

Yeah, that's interesting and my quick bites. I've also got a negative study by chance. We've collected some negative studies but this was in gastric or gastroesophageal junction adenocarcinoma first line volumab and relatilumab plus chemotherapy. It's the phase two relativity 60 study. Big shout out to two Australian authors on the paper, matthew Burge and Neil Tebbert. So this was. Chris talked about a negative study in melanoma with TGIF inhibitor. This is with the addition of a LAG3 inhibitor, relatilumab to Novolumab, in gastroesophageal cancer Again a negative study. But some pre-specified subset analysis suggested that patients with a LAG3 expression score more than 1% may benefit. So I think the answer to this phase two randomized trial is that more studies may be warranted.

Christopher 'CJ' Jackson:

Craig. I thought it was good that they had an IO only arm. That's useful because I think many people want to drop chemotherapy if they can, but it's also very clearly saying that you can't at this stage. So you've got to have a chemo backbone still in first line with esophagogastric cancer, and that for those who are PD-L1 high, be it your CPS5 or 10, whichever threshold you're using, whichever drug you're using, they're really the group that derives the major benefit. I'm sad to see LAG3 is not doing well in this disease subtype and clearly we've got a lot of room to move, a lot of progress to make still in upper GI cancers.

Craig Underhill:

Yes, I agree, Chris, and it's interesting that it's taken us, like what, 20, 30 years and we're still not enriching populations for the target. The other negative study that we talked about presenting was a paper showing the lack of progress in pancreas cancer for 25 years and the need to really go back to the drawing board and stop doing chemotherapy A versus chemotherapy B, sadly, and the need for early referral to palliative care for patients with metastatic pancreas cancer who don't do well overall. We'll list that paper, but we were too depressed after reading it to talk about it.

Craig Underhill:

And then my last quick bite is in a topic close to my heart, which is telehealth, teletrials, and so this is a paper from ASCO, paper from the Rural Health Working Group of the Alliance Clinical Trials Network, published in the JCO, about improving rural clinical trial enrolment and basically guess what it's all about? Telehealth. And so the paper talks about the need to utilise telehealth for screening visits, the need to work across networks to devolve scans and other procedures to networked partners. Involve scans and other procedures to networked partners, clinical trials, and actually one of the kind of more radical thoughts I had and I'm planning to discuss this when I get the opportunity with bureaucrats and funders is actually to start setting some quotas and mandating that a certain proportion of patients recruited to clinical trials are from remote postcodes. So what do you think about that?

Christopher 'CJ' Jackson:

Well, I think that's absolutely great. The Common Sense Oncology movement, available at commonsenseoncologyorg or hashtag CSOncol, is currently developing a patient priorities charter and consulting with patient groups and patient organizations, as well as patients actively engaged in research design, and one of the key principles that's being mooted as part of that charter is that adequate representation is critical and that the patients who are enrolled in trials should reflect the populations in whom the treatments will be used, which includes gender, age, geography, so it's not just metropolitan centres, and it should be appropriate for that, and that will mean more people of indigenous backgrounds, also with comorbidity, and, of course, rural versus urban patients too. So all in favour of better representation of participants in clinical trials, and decentralised clinical trials are a critical way of achieving that.

Craig Underhill:

Yeah, so quotas would be something a little bit more radical, right, but certainly something to think about. And the regional rural population in Australia is about a third. Mandating a third would be probably pretty radical, but if you started making it a quota of 10%, 20%, I think it would be an important incentive for people to include regional, rural and remote patients via telehealth.

Christopher 'CJ' Jackson:

It's always more expensive, though, isn't it, to do those more truly representative studies where you include and recruit more people. That means more centres opening up, and that does cost more. I think we have to look at where we can cut costs in trials in order that the development costs are lower, in order that, also, they can be done in more centres as well. So we have to think about how we can do trials as efficiently as possible and open up those centres, and that trials recruit in a timely way. No one wants to see a 50-patient trial in 30 centres where every investigator recruits 1.5 patients, because, of course, you don't manage your toxicity well with investigational agents that way, and that also limits the generalisability of those agents too. So you do have to have some centre experience, but equally, ensuring that trials are genuinely representative of the population of interest is critical to the generalizability of trial results.

Craig Underhill:

Sure, Chris, I think we're going to run out of time so we could have this debate another time. But that's really not a tele-trial issue. That's a multi-centre trial issue and you're absolutely right, we need to drive down the cost. But I'll also send a link to a paper I can't remember if it was the University of Omaha or Nebraska. They actually showed that there's a substantial return on investment for the use of telehealth to drive clinical trials. So there's an upfront cost to the sponsor in opening up more sites, but you get people onto the trials quicker, you get innovations to the market quicker, so the return on investment to industry and the cooperative groups is actually quite considerable. So you're actually wrong. The cost is actually lower if you look at the big picture rather than just the upfront costs. But, as I said, we could spend a whole episode really talking about tele-trials and decentralised clinical trials and the ongoing barriers that we need to fix. So you guys are heading off on a wine bar crawl now, all for the sake of reducing your risk of prostate cancer.

Kate Clarke:

I think we'll manage one beer before the plane, Craig.

Craig Underhill:

Yeah, good.

Kate Clarke:

Maybe a modicum of cleaning the pipes, perhaps.

Craig Underhill:

So thanks for squeezing us into your schedule then. It's been a great discussion. I'm looking forward to getting this episode out.

Christopher 'CJ' Jackson:

Thanks, Chris Kia ora kā pai e hoa, Looking forward to our special ESCO episodes coming up soon. Yeah, good and thank you Kate.

Kate Clarke:

Oh, thanks, Craig. Always lovely to see you online and, yeah, desperately looking forward ASCO and and I'll come back raving about positive trials, I swear.

Craig Underhill:

Fantastic.

Rachael Babin:

And thank you, rachel. 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. Thank you 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.