The Oncology Podcast

S3 E3 The Oncology Journal Club Podcast: To INFINITY and Beyond! Rethinking Treatment Paradigms and Common Sense Trial Design

• The Oncology Network presents The Oncology Journal Club Podcast • Season 3 • Episode 3

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

The Oncology Journal Club team take a deep dive into three standout papers:

  • Craig kicks us off with a timely perspective on the long-term toxicity of immune checkpoint inhibitors—are we ready to widen the lens? He highlights the need for more comprehensive research on survivorship issues including quality of life, financial impact and psychological outcomes.
  • Kate brings us the exciting results from the INFINITY study on gastric and gastroesophageal cancers which shows impressive complete response rates in dMMR gastric cancers but at prohibitive costs — and poses a big question: are we ready to rethink treatment paradigms?
  • And CJ unpacks the Common Sense Oncology principles for designing better phase 3 trials — Common Sense Oncology principles offer a patient-centred framework for designing and reporting clinical trials.
  • Of course, we’ve also got our Quick Bites—those quirky, surprising papers that made us raise an eyebrow or two. From RNA vaccines in pancreatic cancer to updated ASCO guidelines for small cell lung cancer, it’s a rapid-fire segment you won’t want to miss.

For links to the papers discussed and bios of our hosts, head to the show notes on oncologynetwork.com.au.

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

Speaker 1:

Welcome back to the Oncology Journal Club, your essential dose of the latest oncology research sharp commentary and just the right amount of humor to keep things lively Brought to you by the Oncology Network. I'm your host, rachel Babin, and as always, I'm joined by our Journal Club dream team Professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. In this episode we're diving deep into three standout papers. Craig kicks us off with a timely perspective on the long-term toxicity of immune checkpoint inhibitors. Are we ready to widen the lens?

Speaker 1:

Kate brings us the exciting results from the INFINITY study on gastric and gastroesophageal cancers and poses a big question Are we ready to rethink treatment paradigms? And CJ unpacks the common sense oncology principles for designing better phase three trials, because, let's be honest, we could all use a little more common sense when it comes to trial design. And of course we've also got our quick bites, those quirky, surprising papers that made us raise an eyebrow or two, from RNA vaccines in pancreatic cancer to updated ASCO guidelines for small cell lung cancer. It's a rapid fire segment you won't want to miss. For links to the papers discussed and bios of our hosts, head to the show notes on oncologynetworkcomau. The Oncology Journal Club is proudly produced by the Oncology Network podcast team. Thanks for tuning in. Let's get started.

Speaker 2:

Welcome to episode three, ojc Trans-Tasman. I hope everyone enjoyed our special episode last time about DEI. We had some feedback from people. It was great to get that. Thank you so much, including one avid listener who said that it was the best episode of the podcast that we'd done, which was pretty amazing. She previously had had to stop and pull off the road laughing at a previous episode. This one was a little bit more serious. Not everyone agreed. Some people thought we were probably living in an echo chamber, but that's okay. It's good to have some diversity of opinion.

Speaker 3:

I think it's particularly good, craig, if we're getting negative feedback, it goes to show that we're not living in an echo chamber. It means that we're encouraging multiple views to be heard, and the fact that our listeners have offered a diversity of feedback goes to show we've got a broad listenership, which I think is great.

Speaker 2:

Exactly Now. We're just going to get straight into it. We're back to our regular format. Kate, you've got a long format paper for us. How are you going?

Speaker 4:

No, I'm good. It's sunny in Wellington, which is always a surprise to all of us, so I'm cheating. I'm doing the journal club that I'm doing tomorrow for our journal club at work. So I wanted to talk about Infinity, which provided me the opportunity to use lots of cool toy story memes in my presentation, and it is by I don't know how they say this Gono or Giono, the Italian GI cancer group and inspired by Niche 2 and Nadina. We're using a short duration combination anti-CLA4, anti-pd1, were using a short duration combination anti-CCLA4, anti-pd1, pd-l1 that shows dramatic response neoadjuvantly in immunotherapy, sensitive cancers. So you would recall that Niche 2 was in colorectal DMMR and Nadina was in melanoma.

Speaker 4:

This is a group, it's two cohorts. The first cohort DMMR, gastric, and what they did was just a couple of backgrounds. We already know that people with gastric cancer, that is, mmr deficient, do better anyway. So it's prognostic and there's concern that it's predictive. So they have significantly less benefit to perioperative chemotherapy, though there remains some debate about the use of taxone. So this small trial, two cohorts First cohort they got trimolimumab once and divalumab three times over 12 weeks and then surgery at 15 to 18 weeks. Lots of co-investigator points, looking for markers of response really, other than having two surgeries 18 enrolled. Two patients refused surgery because they got a clinical complaint response and walked away. One withdrew consent due to tox.

Speaker 4:

15 were available for their primary endpoint. Nine had a pathological complete response. Just of note, if you've got T4 disease, only 17% of those had a PCR and 89% in the T2-3 group had a PCR. No, total disease didn't seem to matter. There was only two recurrences out of the 15, but they were the two that you guessed the one that didn't have surgery because they progressed early, and a patient who had heterogeneous disease at time of surgery so turned out to have both deficient and proficient MMR disease and the same cancer Signature. Liquid biopsies if you could make the test, which they could in, about 65% of patients were both sensitive and specific for residual disease at time of surgery.

Speaker 4:

Then the End of Minute Data Monitoring Committee said they could do cohort two. So cohort two was that they did the same systemic therapy and an extensive response assessment regular PET scans, eus with multiple bite-on-bite biopsies, fnaf, suspicious nodes, cigna Terra. If you met their criteria for complete clinical response, which was everything had to be negative, you were then allowed to be put on intense surveillance. Primary endpoint was the rate of clinical complete response in absence of salvage therapy. We're still early. 12-month progression-free survival is 94%. 12-month OS is 100%. 12-month gastrectomy-free survival is only 65%. Early follow-up thus far. It's a proof of concept and fascinating. But I think David Ilsen, who wrote the editorial, and the discussants in the paper themselves were fair.

Speaker 4:

Neoadjuvant IO in surgery is probably massive overtreatment for most. These people are going to do well with one or either strategy and proof that these people probably can in the future invent a chemo-free strategy. The current industry trials are all chemo plus with DMMR patients. Stratified Non-operative management may be morbidity or quality of life improving. But the current cost of this particular drug strategy, at least in New Zealand, is prohibitive. There's $130,000 retail for the drugs alone. So until the drugs get a shitload cheaper we have got a problem. So Tremolimumab not only is it unpronounceable but it's unaffordable at $70,000 for one 300 milligram dose. So there you go.

Speaker 3:

So, kate, I was reading in the Checkmate 8HW study how the people who did poorly early in 8HW when they looked at central versus local assessment of DMMR there was a gap there, and those that only had centrally defined DMMR were the ones who got the benefit. Did the study in particular mandate central assessment of mismatch repair or MSI, or was that all done locally?

Speaker 4:

Not that I read, but that doesn't mean that they didn't. I think they did a lot of referring to supplementary papers which I may have not read. I think the interesting thing, the other thing that they were concerned about, was the two people who didn't have surgery were showing signs of having responded and then loss of response. Were showing signs of having responded and then loss of response. And this is a 16-week strategy as opposed to everybody else's a six-week strategy, and maybe they would have been better served with earlier surgery.

Speaker 4:

I thought that was an interesting call, that there are people who, for whatever reason, respond early and then don't. And the T4 call, I think, is also relevant. You know they're the ones that you're tempted to use and I know this is cross-trial and cross-disease but they are the people that you're tempted to use these kind of strategies in to downstage them, and it turns out that maybe we're not able to downstage them as well as we'd like, and there's a lot of reasons for that, and one of them that's suggested by this author is that by very nature of being T4, the immune environment has changed and so you don't have sort of disease anymore.

Speaker 3:

The colorectal Kate, it's the nodal positivity which makes a difference, isn't it, rather than the T status. The T4 does pretty well, but the T2N1 DMMR does pretty badly. You know, by comparison, the higher the nodal status it goes up, the less protective effect the DMMR is. So there certainly is something biologically distinct about tumours which progress and escape local control if they're DMMR.

Speaker 2:

All right, thank you, kay, for that interesting paper. Good luck with your journal club Good practice. And Chris, you've got an interesting paper, I see, to tell us about Common Sense Oncology Principles for the Design, analysis and Reporting of Randomized Phase III Clinical Trials.

Speaker 3:

Well, this is not quite blowing my own trumpet, Craig, but it's certainly blown the trumpet of the research group. I'm working closely with the Common Sense Oncology group. People know that we had Chris Booth from Queen's University, Kingston, Canada, on last year to talk about CSO, and CSO is a grassroots organisation that was formed a couple of years ago to try to refocus on patient outcomes that matter. This research paper is the development of principles for the design, analysis and reporting of phase three RCTs. Internally we call this the RCT checklist, and on the authorship of this were such international luminaries as Michelle Gawale, Ian Tannock and Elizabeth Eisenhower, who's very well known as head of the Canadian Clinical Trials Group and as the grandmother of Resyst Criteria. So some pretty big hitters on this paper.

Speaker 2:

And Nathan Churney who we've had on the podcast before.

Speaker 3:

Nathan Churney, the Australian as well. Yeah, the father of the ESMO MCBS there's some really big names on this. Let's break this trial down into three parts trial design, trial analysis and trial reporting with what they've checklisted. For starters, in the trial design they said use real-world control arms. Patients deserve current standard of care, not outdated or reasonably substandard therapies, because control arm suppression is increasingly a problem, particularly in clinical trials conducted in low and middle-income countries. Choosing meaningful endpoints of real survival and quality of life, particularly health-related quality of life, should be preferred over soft surrogates like PFS. Unless there's validated surrogacy and when people have done RCTs with PFS as the primary endpoint, people know that if they have low disease burden, perhaps only two or three centimetres of disease can actually make you eligible for a trial. A single centimetre of growth can make you a resist progressor, which may or may not be clinically meaningful.

Speaker 3:

There's a call to ensure that power of the trial is adequate to power for real, clinically meaningful benefit, not just statistical significance, and that trials should be designed to detect or rule out substantial benefit such as meeting the MCBS thresholds. So a priori, making sure that your endpoint is not just going to get a hazard ratio of 0.85 with a 0.001, but it's actually going to meet an ESMO MCBS criteria. Currently there's a trend towards including only the fittest super humans as going into clinical trials, and so there's a call to don't share equipment with patients, to ensure that broad eligibility criteria make results generalisable.

Speaker 3:

Arbitrary age or comorbidity cut-offs are outdated and exclusionary and should be avoided. And plan for fairness. If the experiment of drugs improves survival in later lines, it must be offered to control patients at progression. So basically, plan crossover for drugs which do have proven efficacy in later lines and withholding crossover for where there is no proof of survival gain in later lines, because crossover when you don't have later line activity is not ethical either. Lines and withholding crossover for where there is no proof of survival gain in later lines, because crossover when you don't have later line activity is not ethical either. There's a call. One of the criteria is that censoring must be transparent, that toxicity reporting must be honest and subgroup analysis must be pre-specified. Let's cut out the slicing of the data post hoc to find a flattering result Again. That post hoc comparison stuff, which is no longer corrected and is touted as exploratory analyses in the paper, is often then the headline and the accompanying press release. Let's stop there.

Speaker 2:

I think everyone tends to do that, don't they? Because let me not cast the first stone, but you sometimes go. What about the liver only population? So we all do that, but I think it's important that we don't.

Speaker 3:

It's important meaningfully, but it's hypothesis generating, isn't it Absolutely hypothesis generating? Every trial report should include the absolute benefits, for example, the survival gain in months, not just the relative benefits. Saying a 30% lower chance of death when it's actually a hazard ratio of 0.7 can be misleading for patients, particularly if they have incurable disease. They might think that they are less likely to die if they have this treatment, when actually what it really means is that death is delayed rather than cure. There should be a lay summary written for patients, free of jargon, and the CSO group discourage the use of medical writers paid for by sponsors. So the final word is that CSO is putting patients back at the centre of evidence generation and, in a landscape where too many cancer drugs are greenlit based on marginal, surrogate or biased results, this paper is a call to arms for trialists, editors, regulators and reviewers to raise the bar. And if we're going to make progress in oncology, we need to rebuild trust in the evidence, and that starts with common sense.

Speaker 2:

Fantastic. Thanks, Chris. I think it's a good paper and I think it may actually become a much-used paper, a reference paper, cited paper. Will you send that to your colleagues at the AGITG, for example, Because I think it's a useful reference for cooperative groups and others who are designing studies to think about these issues a priori.

Speaker 3:

Well, cso is engaging with clinical trialists, with cooperative groups and also with journal editors to use the study and also in one of the quick bites I'll talk about shortly, there's a little bit of work we're doing with meetings and research groups, professional groups like ASCO, for example, to get that soon. And, kate, you mentioned the gastric cancer study today. I was really pleased that you mentioned that study because I'm doing a teaching session with the trainees tomorrow so I'll bring that particular study up and also with those trainees. Craig, when we do the AGITG pre-signatureships, we'll absolutely be getting them to use the CSO checklist to evaluate the quality of clinical trials as a framework for helping them understand a randomised evidence. When you're starting out analysing evidence, it can be quite daunting how to understand a trial and I think having a tool like this will be helpful for all people who are getting to grips with understanding and interpreting evidence. I think it's a really good tool and I hope it gets widely used.

Speaker 2:

Yeah, good Thanks for picking it. I think we have a very general listenership and so I think hopefully people will appreciate you highlighting that paper. Kate, did you want to make any comment?

Speaker 4:

Yeah, sorry, I just think very quickly that what I would say is that this just highlights how we have to have non-industry funding in drug trials, because it's just too hard to dance with that particular devil getting all the information, because we all have different needs, you know, and our needs are for patients to get meaningful benefit out of every change in therapy that we make. That may not be the same drivers for some of the people that we're collaborating with, and if we take away government and university or benevolent funding, we're stuck with only one source of money.

Speaker 3:

Kate, are you still on last week's episode?

Speaker 1:

No.

Speaker 4:

I'm stuck in my. I'm in the same room, so maybe that's what it is.

Speaker 2:

I think, kate, you make a good point. I was just going to say, Chris, I was listening to you and thinking, oh, maybe some devious people will be using this as the anti-checklist. I'll be going okay, well, how can I manipulate the endpoints to prove my point? But your next paper, I think, is a way to manage that problem.

Speaker 3:

Yeah, look, a couple of comments around that specifically. I think, for starters, drug companies simply respond to incentives, right, you know? And they're just looking to get their drugs registered and they trust the regulatory authority to make appropriate decisions. And it's the regulators who actually have to set the bar for where things are and actually the regulatory bar has got lower and lower and lower over recent years. We need to reset that regulatory bar and if it's a fair bar for everyone, then the pharma companies will respond to that, because they're just commercial companies who are actually just behaving in a rational way and they're responding to incentives. We need to set that incentive right and the FDA is the way to do that.

Speaker 3:

The quick part I wanted to talk about follows on from that. It's a related paper, but not the same. It is again from the CSO group. That's how to critique a trial without the spin. So this is a common sense oncology checklist on how to discuss phase three cancer trials at major meetings.

Speaker 3:

This paper lays out a structured approach. Number one start with the context. Was the trial asking the right question for the time? Has the standard of care changed since? Number two interrogate the design. Was the control arm optimal? Were the endpoints like overall survival or quality of life, or were weaker surrogates like PFS used?

Speaker 3:

Scrutinize the analysis Were treatments delivered evenly? Was there any imbalance in dropout, censoring or unplanned subgroup analysis? And then zoom out and ask questions like does this result offer meaningful clinical benefit, not just a positive p-value? Consider toxicity, quality of life, cost and feasibility. The authors recommend using objective tools like the ESMO MCBS and urge discussants to avoid soft language like toxicity was manageable. In their presentations. They actually report patient-centered outcomes and I'd really like to see people reporting quality of life at the same time as a primary endpoint. Unlike the earlier CSO checklist paper, which targeted trial design reporting, this one focuses on how to publicly interpret trial results with integrity. Live on stage under pressure. Bottom line, if any of our readers is asked to discuss a new RCT at ASCO or ESMO. This paper gives you a patient-centered, evidence-grounded roadmap, but I must say yeah, form a queue, right.

Speaker 2:

Yeah, that's right. Asco, I'm available If you need me, I'm here. All right, good paper. Thank you, Chris. Do you have one more for us?

Speaker 3:

Yep, one more quick bite here's my notes, I'm actually very prepared this week, while he's flicking through.

Speaker 4:

I remember going to one ASCO where there was a stark negative trial for something unmentionable, because it would be identifiable who the discussant was, and the discussant stood up and said, yeah, that was three negative trials, but this is a strategy that I will still be using. And you're like mate, goodness sake.

Speaker 3:

My third quick bite is my third paper is a paper called radiofrequency ablation versus stereotactic body radiotherapy for recurrent small hepatocellular carcinoma a randomized open label control trial published in jco. This is a head-to-head phase three trial comparing two common treatments for recurrent small HCC RFA and SBRT. First comment RFA is probably not what we use so much in New Zealand or Australia. We tend to use a microwave ablation and we can talk about that a little bit more. But this is comparing an ablative therapy with serotectic body radiotherapy. This was a randomized open-label trial from China involving 166 patients with solitary recurrent HCC under 5, cm, mostly hepatitis B, and patients were randomized one-to-one to receive either RFA or SBRT, with the primary endpoint being local PFS. The results were that SBRT clearly came out on top for local control, with the two-year local progression-free survival being 92.7% versus 75.8%. With RFA is a ratio of 0.45. That's quite strong and this result was even more pronounced for small tumors under two centimeters. But even though local progression-free survival was better overall, pfs was no different and overall survival was not different between the two groups, probably because of other tumours popping up in the liver or the orbit of interest of the liver still failing overall. So good local control but not necessarily improving PFS or overall survival.

Speaker 3:

What does this mean for practice? For sultry recurrence, small HCC, particularly under two centimetres, sbrt seems to be better than RFA. Whether SBRT is better than microwave ablation that's still an open question, but it is a compelling alternative when RFA is limited by tumor location or visibility. It's non-invasive, it's precise and it's repeatable. But survival outcomes are similar and you can still use either one. But of course RFA and microwave still require an anesthetist, an ultrasound machine and experience. So that to me says that there's a growing body of literature now around using SBRT, not just in colorectal and liver metastases and difficult areas, but also other small lesions. And if you've got a small tumour under five centimetres or even under two and you've got good access to SBRT, then that could be an option for people in whom local ablative therapies may not be available and part of a growing trend of decent research coming out of China.

Speaker 2:

I would have thought that the access to SBRT is probably better than RFA. I think that there are centres regional centres in Australia, bigger regional centres are able to offer SBRT with certain tumours and they're not able to offer RFA.

Speaker 3:

Yeah, I think there's some places, certainly in lower, middle and young countries, where hepatocellular carcinoma is very prevalent, where access to radiotherapy actually isn't that good. So I think we have to be cognizant that we still live in a high-income country where we've got good access to radiation therapies.

Speaker 3:

Both of us. Craig, I think you and me both have got good access to radiation therapy, but that's not universal and I think that ablative techniques still remain an important part of the armamentarium in places where access to SBRT may not be possible, and access to radiation is still a real luxury for many parts of the world.

Speaker 2:

Fantastic. All right, I have a paper to tell you about my long paper. I've picked out one from JAMA Oncology. It's very recent, called Long-Term Toxicity of Immune Checkpoint Inhibitors Time to Widen the Lens. It's actually a viewpoint or an opinion piece, pointing out that there's now over 60 indications, in the US at least, is monotherapy or combination with systemic therapies for immune checkpoint inhibitors. So they've really become into widespread use and we've talked lots of times about various issues regarding immune-related adverse events. Point out that there are a number of papers.

Speaker 2:

A recent scoping review of survivorship outcomes in patients treated with ICIs included 39 clinical cohort studies, mainly in non-small cell lung cancer and melanoma. In this analysis, impairments in quality of life and psychosocial functioning were consistently observed and there was a paucity of data assessing other survivorship domains, such as long-term treatment effects, fertility, return to work and stress. The need for broader evaluation of survivorship. Financial toxicity was highlighted, as also time toxicity, because people are often on these treatments for a year or two. Now it is a bit of obviously a bit of a plus that people are alive with lung cancers and melanomas and able to have long-term toxicity. But you know there's some issues about us being aware of them and how to manage them and how to quantify the problem when we're talking to patients about going on to treatments.

Speaker 2:

And so their suggestions is that clinical trials assessing checkpoint inhibitors in the curative setting need to incorporate and report longer-term data on immune-related adverse events. So a longer period of collection of information about side effects and reporting of that. Collection of information about side effects and reporting of that. They suggest that registry data could be used to quantify the incidence and spectrum of immune-related adverse events. Registries are actually quite difficult to set up and to run to enter data, but that's one option.

Speaker 2:

And lastly, they suggested expanding on research to address a broader range of survivorship issues for patients treated with ICIs. So we don't have a lot of information, so we should be looking at prospectively researching particular impacts of long-term side effects, including on quality of life, financial toxicity, psychological outcomes, sexual function, fertility and other long-term outcomes. So really a call to action for us to, in this new, brave new world of people living longer and surviving cancers, of us collecting more information about long-term impacts of that treatment. Just as we would have done that two decades ago, three decades ago with chemotherapy, we now probably need to be thinking along those lines with ICIs. So just, and I thought it was an interesting viewpoint.

Speaker 3:

Such a great point, Craig, isn't it? I mean, it's just so important to get that long-term data you know, particularly when you're using it in the adjuvant setting, such as renal cell carcinoma, for a benefit that could be described as marginal at best, or even in adjuvant melanoma, whereby we don't actually have OS data yet. So understanding the long-term toxicities you can understand the real trade-offs, is just absolutely and utterly critical. Craig, do you think registry studies are the way to go? I've got a few worries about registries in terms of how well they accurately do measure long-term toxicity.

Speaker 2:

Yeah, so there's registries and there's registry studies.

Speaker 2:

Registries are collecting information prospectively and being able to interrogate it, generate hypotheses that could lead to future research. Registry trials are simple trials, often answering real world questions, and it might be two standard treatments involved in a randomized way with minimal data collection. Really looking at you know important endpoints such as overall survival, quality of life, often, often studies that are unable wouldn't be done by pharma because it's two standard of care treatments that are registered. And so in Australia, the Walter and Liza Hall Institute is probably leading the pack there in researching on registry trials and implementation of registry trials. They're working with us on our large medical research future funded revitalized program and bringing some of these real world studies to the regions, and some of the smaller sites that are new to our network are reporting. These are actually a really good way for them to test the capability of their unit and their processes are in place before they take on a large pharma-sponsored complicated study. So it's actually a really good way for some of the smaller sites to get into clinical trials. Kate, you're looking puzzled.

Speaker 4:

So I get that that's an advantage to the unit and will hopefully advantage their future patients because they will have better trial capacities. But not wanting to call out, but everybody knows the names of the 800 or 900 trials in a couple of immunotherapy drugs that we have. Currently that data is being collected. If it isn't being collected beyond five years, that's on the people selling the very expensive drugs.

Speaker 4:

I am incredibly nervous about our young women in their 30s having immunotherapy in their 30s for a 5% survival benefit when the vast majority of those women will be alive into their 80s If we're not collecting good data about their long-term outcomes. And I don't want to frighten anybody but multiple sclerosis, all of those things that are female heavy, it's starting to give me the wibbly wobblings. I actually think we have to say yeah, that's great, craig. I really like the idea of registry trials to train people how to do stuff. But the onus on this very expensive long-term data must be on the companies who are making a lot of money out of these trials with very small p-value important benefits.

Speaker 2:

I'm not disagreeing with you. Kate Bruce was just asking me about registry trials. So I think the registries are important and I think mandating some long-term collection of toxicities is important as well.

Speaker 3:

We need to find some areas where we disagree a wee bit more, otherwise we'll end up sounding like an echo chamber. I think that, Kate, I really agree with you. Damn it, I agree with you.

Speaker 4:

I need to disagree with you a little bit more.

Speaker 3:

But I think that the radiation oncologists do this really well. You know they did the late effects studies really well and they do follow people up beyond 10 years or even to 15 years with the breast cancer studies, for example, looking at lymphedema rates and cardiac disease, et cetera, et cetera. And also child cancer has done this extraordinarily well also, and it's an area where actually medical oncology has fallen down. I mean, I think we know the five and 10 year data maybe, but that's it in terms of efficacy. But you don't usually get follow up data for toxicity beyond five. So I think that is an area where we may need to sharpen our pens and you could potentially tie some regulatory decisions to the long term provision of tox data. And we're not short on tox data in the first five years. We've got a heck of a lot of that.

Speaker 2:

But I agree with you completely we don't have much the way of long term, I agree, heck of a lot of that, but I agree with you completely we don't have much the way of long term, I agree. All right, let's move on. I just want to note Christopher praises radiation oncologists, episode three for OJC. But you're right, they did do it well. Look, it's a brave new world, right? We've got more and more people surviving cancer. It's fantastic. But we may need the systems level change to start collecting that long-term toxicity data in a more rigorous way.

Speaker 3:

Yeah, I'll get them to add that to the next CSO checklist. Craig, how long was the follow-up for toxicity?

Speaker 2:

Yeah, why not Version two?

Speaker 3:

Suggestion Great ideas happening at the Oncology Journal Club podcast.

Speaker 4:

Yeah, that's it, kate, I've just got one wee short paper. It is from Memorial Sloan Kettering Professor Bill Chandran's lab, published open access in Nature in February 2025. Just a heads up those of us who don't have academic posts in New Zealand can only rely on open access. We've had all our journal access taken office in the public health sector. Chris is raising an eye because he's Professor Jackson, so he's still got university attachment. It's very expensive, craig.

Speaker 4:

This was using mRNA vaccines in pancreatic cancer. You've heard this drug before autogene sevumaran, which is a somatic mutation-derived neoantigens. So you have to first make the vaccine, then you give it to the person and the people in cancer specific. So it's a phase one trial. All patients got surgery, t-zolizumab and their version of autogen 7-Moran however you say that and modified falvorinox.

Speaker 4:

And then they looked at a couple of things. They looked at who actually responded. They were defined as those who still had detectable CD8 positive T-cell clones at different time points. They then looked at the great thing about pancreatic cancer is the sad thing about pancreatic cancer you don't have to wait very long to get your follow-up. So median follow-up of over three years. Those who responded and it was 50-50, only two of them have relapsed. The non-responders five have already relapsed. And of course, those of us who look after pancreatic cancer may be curious to understand that actually the median OS hasn't been reached yet, so maybe there is a delayed effect. It's absolutely beautiful paper defining their methods, lots of concurrent exploratory analysis, including an attempt to explain why two responders then lost immune control and how we could prevent that happening in the future, and pushes a couple of buttons from last week NIH funded research, cooperative group and mRNA vaccines. But there you go, so it's a beautiful paper.

Speaker 2:

We could possibly do a whole segment, a whole podcast on mRNA vaccine. So it's a really interesting field and let's hope that it is another area of progress. I've got two papers just for us to wrap up this episode One was we like guidelines, don't we? Asco Rapid Recommendation Systemic Therapy for Small Cell Lung Cancer. Asco Guideline Rapid Recommendation Update, in which they added from the Adriatic study they've added Divolumab as a standard of care for patients who received platinum-based chemotherapy for limited stage small cell lung cancer. So they're suggesting that they should receive tovolumab after. There's a nice little treatment algorithm in the paper as well, and this is now available on the PBS in Australia. I'm not sure. I hate to ask whether that's available in New Zealand as yet for small cell lung cancer. You guys don't treat lung cancers. That was maybe an unfair question. I think we do have tovolumab for non cancer. You guys don't treat lung cancers. That was maybe an unfair question.

Speaker 3:

I think we do have divilumab for non-small cell, don't we?

Speaker 2:

We can clarify that, maybe for the next episode, but that's certainly now available in Australia. That study on which it's based showed, I think, a clinically meaningful overall survival difference, chris I think a clinically meaningful overall survival difference, chris which was 33 months for placebo and 55 months for the Divilumab patients. So that's what's at 22 months and nearly two years overall survival. I think that's probably we'll accept that under the CSO system.

Speaker 3:

I think under ESMO MCBS it'd be a five, wouldn't it Craig? That'd be like pretty high line, yeah, probably.

Speaker 2:

And the other thing I just wanted to end again. It's a bit of a positive note. This Cancer Statistics 2025, this is an annual publication from the American Cancer Society. So this is US data. But just looking at incidence of mortality for cancer over the years for the American population, so cancer mortality rate continued to decline through 2022. So since 1991, that's meant they've got some interesting graphs looking at from 1991, really a flattening of the rise in mortality versus where it would have continued to go on the rate of increase in the past and so over that decade saved about four and a half million deaths in the US.

Speaker 2:

So I did some population extrapolations for Australia. Sorry, I didn't know what the population was in New Zealand so I couldn't do that, but it was for the Australian population. Over that period of time, if it's the same benefit, it's about 350,000 deaths averted and that's been mostly through smoking reductions, earlier detection for some cancers and improved treatment. So I think we're starting to see the impact of some of the immunotherapies and other targeted therapies and other treatments. The overall cancer incidence is generally declined in men but it continues to rise in young women and that's mostly through the hypothesis there is mostly through tobacco control Hello New Zealand.

Speaker 2:

And the lung cancer incidence now surpassed men, especially in those under 65. There's still large disparities in the Native American populations and the African American populations and disadvantaged populations. So there's still a lot of work to do to bring, to look at equity issues and to drive those disadvantaged populations up to that of the white and more privileged populations. But I think it's always interesting just to take stock and have a look back and to see really, you know, over a period of time, how much improvement there is through the kind of multiple programs, multiple efforts to reduce the impact of cancer.

Speaker 3:

That's right, craig. I mean, cancer control is not a silver bullet. It takes multiple small gains to see that curve turn around, but it is good to see that we're not finally losing battle. We're making small incremental gains, and one of the big issues with cancer control is that the benefits aren't felt evenly, and that's a point that you've raised there and I agree with that entirely. We need to make sure that the interventions that we have and the preventions that we do reach all people equally in the professions that we do reach all people equally, otherwise that equity gap will just keep getting bigger.

Speaker 2:

That's right, wonderful, all right. So a bit of a hoi polloi, as usual with Cook's tour of oncology. Lots of interesting papers. I hope people find that useful. If people identify interesting papers they'd like to have discussed, please let us know and continue to give us your feedback on this episode and others. Thank you, dr Clark.

Speaker 4:

I've got to head because I've got my other job now, being chief mum and bottle washer.

Speaker 2:

So see you later. Count out and thank you Rachel, our producer Extraordinaire.

Speaker 1:

Always a pleasure, thank you.

Speaker 2:

And we'll see you next episode. Won't see us because it's a podcast. You might hear us. Sorry, I'll do that again. To podcast.

Speaker 3:

You might hear us. Sorry, I'll do that again, that's alright.

Speaker 2:

I can finish it like that Craig, you've got to take the piss of your last time. I know, I know you can even leave that bit in.

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. Thank you, 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.