.png)
The Oncology Podcast
The Oncology Podcast including The Oncology Journal Club Podcast by Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson; and Supportive Care Matters by Dr. Bogda Koczwara.
Oncology News and Expert Analysis from a unique Australian viewpoint.
Proudly brought to you by The Oncology Network.
The Oncology Network are producers of digital resources that support busy oncology health professionals. For more information visit our website www.oncologynetwork.com.au.
We also invite Healthcare Professionals to subscribe to The Oncology Newsletter and our Oncology Portal for free and exclusive resources at: www.oncologynetwork.com.au
The Oncology Podcast
S3E6 The Oncology Journal Club: Breast Cancer Treatments, Non-operative Management, Clinical Trial Standards, Fertility and Hope
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
Welcome to Episode 6 of The Oncology Journal Club podcast. This is where we take a famously different approach to oncology research.
Has non-operative management finally found its place in treating certain cancers? This episode unpacks compelling new data that might challenge the surgeon's traditional role for some patients with mismatch repair deficient tumours. While rectal cancer patients show remarkable complete response rates to immunotherapy, the story gets more complex across different cancer types – raising fascinating questions about tumour biology, patient selection and the future of organ preservation.
We explore the delicate art of discussing immunotherapy outcomes with patients, navigating that narrow path between hope and realism. When treatments occasionally produce dramatic responses but more commonly offer limited benefits, how do oncologists communicate effectively without creating unrealistic expectations? Our hosts share practical strategies for these challenging conversations, emphasising that truly patient-centred care requires ongoing dialogue about prognosis.
The oncology research world is evolving too, with updated CONSORT and SPIRIT guidelines transforming how clinical trials are designed and reported. These frameworks now mandate greater transparency, clearer safety reporting and increased patient involvement in study design – potentially leading to more trustworthy and applicable research outcomes.
Plus, we examine an intriguing Chinese trial showing remarkable survival benefits from low-dose continuous capecitabine combined with aromatase inhibitors for metastatic breast cancer – a potential game-changer for resource-limited settings.
From this year's AACR meeting, we highlight what might be the first change in standard of care for locally advanced head and neck cancer in two decades, along with promising targeted therapies for specific molecular subtypes of lung cancer.
Join our expert hosts Professor Craig Underhill, Dr. Kate Clarke and Professor Christopher Jackson as they navigate these developments with their trademark blend of critical analysis, clinical wisdom and humour.
Subscribe to The Oncology Newsletter to stay informed about the evolving landscape of oncology care and research.
For links to the abstracts and bios of our hosts, head to the show notes on oncologynetwork.com.au.
The Oncology Podcast - An Australian Oncology Perspective
Welcome back to the Oncology Journal Club, your essential dose of the latest oncology research, expert analysis and our trademark blend of healthy skepticism and bad dad jokes, brought to you by the Oncology Network. I'm your producer, rachel Babin, and I am once again joined by our Journal Club hosting dream team Professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. This week we've got a powerhouse lineup. Cj has huge news he has taken up the challenge of not covering GI this week. He takes us inside a compelling study exploring non-operative management of mismatch repair deficient tumours. Kate covers metastatic breast cancer with the MEKA trial and Craig walks us through not one but two major updates to clinical trial standards. What's new, what's helpful and what does it all mean for how we read and write trials? Of course we've also got our signature quick writes those curious, quirky papers you won't hear about anywhere else. You'll find links to all of the papers and the host's bios in the show notes at oncologynetworkcomau. The Oncology Journal Club is proudly produced by the Oncology Network's podcast team. Thanks for tuning in. Let's get started.
Speaker 2:Hey g'day g'day. Welcome to OJC Cross the Ditch. Hello, dr Clark, how are you?
Speaker 3:Hey Kia, ora I am not blown away, despite the 140 kilometre hour winds outside my door.
Speaker 2:Windy Wellington, living up to its name, and Professor Jackson how are you?
Speaker 4:Yeah, I'm really well. Thanks very much, craig Kia ora audience Kate. I was hearing today that today was the windiest southerly in Wellington's history, which means that there's a northerly, easterly and a westerly which have been stronger.
Speaker 3:There would definitely have been a northerly. That's been stronger because, as you know, that is our predominant wind, but coming from Auckland at speed. But yes, it has been quite dramatic and many of the coastal roads are closed.
Speaker 4:Yeah, well, we know. The reason that Wellington blows is that Christchurch sucks, yeah.
Speaker 2:I would have thought most of the hot air comes out of the needed.
Speaker 4:It's just out of my ass streak.
Speaker 2:Where Professor Jackson is compoding, that's it All right. Where Professor Jackson is composing.
Speaker 4:All right On to the data.
Speaker 2:Yeah, and so thanks everybody for recent feedback on the episodes. It's good to know that someone other than my mother is listening. Professor Jackson, let me guess something about GI cancer.
Speaker 4:Well, you gave me a total embargo on GI cancers this time, craig, so I've got a couple of things which are non-GI cancer related. My main paper today is the Non-Operative Management in DMMR Solid Tumors. This is just out in the New England Journal of Medicine, lovingly known as the Journal of Positive Results. We will all remember very well the dostalalamab story which came out of the Memorial Sloan Kettering, initially with nine patients who had rectal cancer, who had a year's worth of dostalamab, who had clinical complete responses. And then we saw the headlines, which were researchers have tears of joy at these wonderful responses based on nine patients and the standard of care being changed with such a small number of patients. A lot of hoo-ha. And was that an abstract? Was that the plenary askers? Well, I can't remember if it was the plenary or not. I think it might have been.
Speaker 2:I think it might have been.
Speaker 4:But it was a big deal, wasn't it at the time, and particularly for a tumour type where all we were really doing was a modality shift. We weren't actually curing increased rates of people at that time. So the questions at that time were was it actually going to be a durable response? Were you curing more people or was it around saving the morbidity of abdominal perineal resection? Turns out that that particularly Dostalumab study was part of a bigger project. So they had a two-cohort study, one for rectal cancer only and the second cohort was for any patient with a localized so non-metastatic stage 1, 2 or 3, any primary tumor site with deficient mismatch repair as judged by immunohistochemical loss of expression of one of the four mismatch repair proteins. So it did not have to be microsatellite instability proven by NGS, it just had to be loss of expression of mismetropia proteins, which is imperfect but it's one we've got in routine clinical practice. This is in the background of neoadjuvant studies such as the Niche study, which is one of Kate's favourite studies, which I think showed a 70% major pathologic response in people who just got a couple of doses of immune therapy, and the docetalimere-brectal study, which now I think we're up to about 30-odd patients in that study with 100% clinical complete response at 12 months, don't have the long-term data or morbidity. And these patients remember, with mismatch repair deficient cancer usually have a better prognosis than those with microsatellite stable. So for most of these patients this is a non-surgical approach or a modality switch rather than necessarily a cure. And there's a very big difference in a right hemicolectomy from an APR. So the balance of risks and benefits in all tumours is not the same.
Speaker 4:So this is a phase two study. At one institution Patients with DMMR got 500 milligrams of dostalumab every three weeks for nine cycles or roughly six months Cohort 1 rectal. Cohort 2 non-rectal solid tumors, and they were evaluated at the conclusion of their six-month course of treatment and eight weeks following. They undertook what they described as all feasible assessments, which would mean endoscopy if appropriate and, one presumes, pet-ct scan as well. But that was in the sub-medicinal materials that I didn't dive into. The primary endpoint of the study was simply for the rectal cohort, not for the all-comers cohort, and the endpoints in the all-comers cohort was exploratory. So just to clarify, this is a phase two single-arm study with an exploratory endpoint. In the New England Journal of Medicine there is hope for my single-institution studies. Yet A Simon two-stage design was undertaken.
Speaker 4:If four or fewer recurrences were noted, then the study was closed with futility. If 13 or more had a little complete response out of 15, it was deemed a success and it was closed for success. And at the end of the 15 patients recruited in cohort two, it was deemed a success as they stopped. Is they stopped? They reported 54 patients in cohort 2, and 19 out of 54, so that's 35% did not have a clinical complete response. So let's just make sure we get that figure clear in our heads.
Speaker 4:100% of people with rectal cancer had clinical complete response and only 65% of people with other solid tumors two-thirds had clinical complete response. Of other sites Now, of those patients, 16 of the 19 who did not have CCR when he was surgery and 3 of 16 had nodal positivity with a primary complete response. So sometimes you might see, for example, a luminal complete response, but you get a nodal positivity. So just assessing the nodes sorry, just assessing the primary site may not be sufficient. And the overall outcomes are the two-year RFS was 96% in cohort one and in cohort two it was 85%. So again, that's not stage stratified stage one, two and three, that's all come as 85% two-year recurrence-free survival.
Speaker 4:So not all patients who have DMMR tumors who get surgery of course remain recurrence-free survival. So not all patients who have DMMR tumors who get surgery of course remain recurrence-free at two years and they can be salvaged with immune therapy at that point. But it does say that we can save about two-thirds of patients from an operation, but a third will still need to have an operation. So despite the fact that immune therapy has got a quote-unquote tumor agnostic indication for DMMR tumors, this study still suggests, in my opinion, that this primary site of tumor does matter. When you're advising people about whether or not you can undertake non-operative management, the two-thirds gives you a ballpark, but we need more information about the specific subtypes as to which tumors respond well and which primary sites do not respond well. But I think this does give appropriate caution and appropriate pause when we're thinking about charging down a non-operative route for all patients with DMMR cancers. This says that we have to be a bit more cautious than that and we can't extrapolate those amazing final in rectal cancer to every single other study.
Speaker 4:So great that we've got that data. It's a little bit more than we had before. Still looking forward to having even more and a really good set of data to have. In my practice recently I've had a very elderly lady who had a number of comorbidities, who had a DMMR colon tumor and the operative risk was thought to be about a 10 to 20% chance of mortality. So she opted for immune therapy and it's now good that we've got data where we can actually say what the chance of CCR is in individuals like that, but clearly not the right operation for everyone, not the right procedure for everyone, and there would be some tumour sites where I might still prefer surgery over six months or more of immune therapy with intensive surveillance. Kate, what's your take on that study? I know it was one that you were with interest too.
Speaker 3:How do I put this in words? After a day on the couch, my feeling is that DMMR-ness is different in each. Why our cancer has MMR deficiency seems to be different in each site and we are still doing this as a massive cohort, so we're not thinking are Lynch-associated different? Are sporadic different? Are the different genetic mutations different? We know that you get heterogeneity in many tumor types.
Speaker 3:That was the gastric cancer trial we talked about last time. Does that explain all of it? Probably not. Or is it just that you need to give a longer time for some tumor types and a shorter time for other tumor types? Should we be giving dual antibodies? Because, particularly the hepatobiliary ones, it's very immune cold. You wouldn't be expecting an anti-PD-1, anti-pd-l1 agent to act particularly well as a single drug in those sites. So there's so many questions out of this, but I think it is very interesting data. I am a fan of Niche2 because they all still get operations and we do have a collection of people who would otherwise be inoperable who are then rendered hopefully in my tiny cohort cured. So that's my take.
Speaker 4:Yeah, so in the rectal cohort they were almost all Lynch patients, weren't they? Kate?
Speaker 3:I was trying to furiously read that now to try and figure that out, because they don't have the very obvious what you'd like to see, which is a mismatch for PRG with pathogenic Lynch syndrome associated germline variants. And then they've got gene but you have to extrapolate out that 50% of them do not have a germline mutation, I think if I've done the maths right. So it is a bit tricky to try and figure out who's who.
Speaker 4:Yeah, and cohort too yeah.
Speaker 2:So, if it's possible for me to get a word in here, chris, a couple of questions. So to me it just sounds interesting, data, thought-provoking, but clearly you can't make a decision on multiple tumours, the management of multiple tumours, on the basis of 60 patients, even if it is in the New England Journal, and so that's a comment. The question is how are you able to access the drug for the elderly lady with a high risk of surgical mortality? Did you have to purchase the drug or were you able to access it now?
Speaker 4:With my particular patient. She opted to self-fund in her instance, although if you've got rectal cancer the company will give you dostalamab if you've got rectal cancer under access program in New Zealand In terms of, is 50 or 60 patients enough data, craig? I mean I think there was extraordinary enthusiasm for rectal cancer non-operative management on the basis of nine patients. So oncologists are not well known for undergeneralizing from early data. I think we're probably more known for overgeneralizing from early data. I think we're probably more known for overgeneralizing from early data.
Speaker 4:I would simply reflect that DMMR in different tumors is clearly different and so you can't extrapolate from rectal. And, like Kate says, I think you have to know a little bit more about the molecular heterogeneity and the origins of that and tease that out. Now we know in advanced. Remember when the very first data came out in DMMR colon cancer? That was from a basket study and there were only about three or six patients with colon cancer in that study, I think from recollection, and people were charging straight in and it was a couple of years before we got you know 177, which was the colorectal-specific one. So I think you have to be cautious. But people will always say you know, we will use the data that we have and we will have evidence-informed practice rather than evidence-constrained practice, and people will make individual decisions with the patient in front of them, provided they are well-informed of the risks, benefits and alternatives. But that does segue slightly into.
Speaker 2:Yeah, but there's like one patient with cholangia carcinoma. So I think you know how to manage cholangia carcinoma the DMMR now on the basis of one.
Speaker 4:Well, I don't think so, Craig.
Speaker 2:Okay, let's move along. Kate, while you're lying on the couch, what have you been reading in your journals?
Speaker 3:Yeah, look, I wanted to present a Chinese trial because it intrigued me. So, from the sublime to the ridiculous. So I think Chris wants to spend. I think the Stalimab resale is about a quarter of a million dollars a patient. So I want to talk about treatment naive metastatic breast cancer using a combination of very low dose capecitabine and an aromatase inhibitor versus the aromatase inhibitor alone, of very low-dose capecitabine and an aromatase inhibitor versus the aromatase inhibitor alone. So this does fall into the trap of combination therapy versus sequential therapy and they have a missing arm. Dr Jackson, if you shuffle another paper, I will torpedo you from here.
Speaker 2:Yeah, Chris, it's like the pandemic started five years ago. You know the button there has got a little hash on it. It's the mute button.
Speaker 3:He's too used to being the professor, anyway. So a group of women medicated ER-positive breast cancer. They were either given very low-dose capecitabine, so 500 milligrams TDS, so three times a day. So 1.5 gram total a day continuous alongside standard dose.
Speaker 3:Aromatase inhibitor versus aromatase inhibitor alone Doubles the PFS. Curiously doubles the five-year OS, which I find fascinating. But nowhere in the paper or the supplementary is there post-protocol treatment. So I can't see whether everybody got access to capecitabine because it's a very standard until we had CDK4-6 for people to have an aromatase inhibitor followed by capecitabine. And we know that capecitabine is very helpful in women with metastatic breast cancer, particularly hormone sensitive, but it is limited by toxicities at our standard doses.
Speaker 3:So I've moved in my practice to do the 1.5 gram BD week on week off protocol and it is fantastic, much easier to deliver than the 2.5 grams per meter squared two weeks on one week off schedule. The other thing I think that was great about this paper was not only was it done in China, but it clearly points out that CDK4-6s are still prohibitive for most of the world and Cape Cider is cheap as chips. So this is an alternative strategy and of course they're now muttering in their discussion about whether this could be moved into an adjuvant space. So I have questions for the authors, but I found this fascinating.
Speaker 2:So, Kate, that dose. Is there some randomized data comparing the two dose schedules and showing some equivalents? You know?
Speaker 3:Yep, so not this dose. So the dose I'm talking about the 1.5 gram VD week on, week off has been compared with the traditional schedule. It's more deliverable and it has a slightly longer PFS, but that's slightly probably because of deliverability. Women don't drop it because their hands are falling off. No, I haven't seen this dose compared with anything else.
Speaker 2:They're using this paper, so will you be changing your practice as a result? Do you think?
Speaker 3:Are we allowed to say things like this? I have sneakily once given somebody hormonal manipulation at the same time as capecitabine because she had her back against the wall and it was before CDK4-6s and she didn't do very well anyway. You know, it's unusual that there would be a woman who wouldn't be appropriate for CDK46, for whom I would also think that Cape Sight of him was a good idea. So I'm not sure where this would fit in my practice, but I do find it fascinating.
Speaker 2:So, chris, if you touch that button again, it'll unmute you. Do you have a question?
Speaker 4:Look, I've just been sitting here quietly off, mute. Actually, craig, and you'll never know it, I'm a quiet little mouse. I thought you was, as we used to feel noise anyway. So, kate, interestingly, the hormonal manipulation that's supposed to stick cells into gene, right? So why does that work with a cytotoxic chemotherapy which is about well, there is a whole page in the article of the introduction.
Speaker 3:Try to explain that to me in a way that I have to say I would need to read again to understand. So the idea is actually that metronomic chemotherapy, particularly capcitamin at these low doses, is not in fact acting on proliferating tumor cells. It's supposed to be acting as an anti-antigenic, anti-cancer therapy promoting apoptosis of the cells within the tumor microvasculature, and I love the sentence anti-cancer therapy, promoting apoptosis of the cells within the tumor microvasculature, and I love the sentence no-transcript, full stop. So so I think it works, but we don't know why it works, is the question. Yeah, okay, but also again, I wonder about heterogeneity. You know, if you take a breast tumor, you know that some of it is er positive, some of it is not. We don't actually know whether we're treating that, whether even our aromatase inhibitors are treating the, the cells that stained er positive, or whether they change all the time. We suspect they change all the time yeah yeah suspect they change all the time.
Speaker 4:That's hard to know, but the great thing about clinical data is that's the final proof that it does work or not, which is what I learned about clinical trials.
Speaker 3:I also want to defend myself, because it is a combination versus a single, but the OS is stonking and so you know no business about crossover or whatever.
Speaker 4:They just proved an OS, which is odd becausedk 46 has only just been able to prove some ultimate endpoint live longer, live better all right.
Speaker 2:Well, thanks, kate. I'm going to change direction, uh, and go a bit lateral, which we like to do on this uh podcast as well, and I'm just going to highlight to people the new CONSULT 2025 statement, an updated guideline for reporting randomized trials, published in Nature Medicine recently, and so the CONSULT guidelines are used for reporting randomized clinical trials or actually not randomized trials, reporting all trials, first published in 1996, updated in 2001, 2010, and now in 2025. And so it's a framework for authors to report clinical trials. Some additions there's a whole list, I think, of 34 checkpoints for people to tick off, a checklist of 34 things to include more information about safety, reporting of potential harms to the subjects, including more clear information about comparator, the intervention, how the intervention comparator actually delivered, details about concomitant care and some importantly, some information about the statistical analysis. Sometimes that can be a bit unclear in reports, so there has to be some detail, either included in the report or in an appendix, and some clear information about potential conflicts of interest. So I thought that was worth highlighting.
Speaker 2:There's a whole series of papers then that were published at the same time, some in other journals such as the BMJ, which were really commentary pieces or perspectives. Some talked about how the process of coming up with these guidelines but an interesting comment in one of the commentaries about the importance of the future of health research do really depends on our ability to produce evidence that's not only innovative but also trustworthy. Reporting guidelines are pivotal to this endeavour. They not only improve research but also help to safeguard public health, and so, by mandating their use, streamlining their implementation and investing in education and technology, reporting guidelines can be transferred from optional aids or administrative hurdles to essential instruments of scientific integrity, really to mandate the use of these frameworks to ensure robust, clear reporting so that people can trust in the information presented.
Speaker 2:So at the same time, another paper appeared called the Spirit 2025. And so this is a similar framework, and this time this is a checklist designed to ensure robust design of clinical trials. So you have the spirit for the design, the consort for the reporting, and in a recent episode, professor jackson talked about common sense oncology guidelines. They're specifically for randomized clinical trials and he also discussed should any of us listening be asked to do a plenary presentation at ASCO on how to discuss randomized clinical trials at major meetings. So in the last couple of episodes in the notes, people can reference these important frameworks for the design, reporting and discussion analysis of clinical trials. I'm sure Professor Jackson will have a comment.
Speaker 4:My first comment is I'm just asking my daughter to say turn off the music, it's really loud. So look, I think reporting clinical trials standards is really critical. The Common Sense Oncology group clearly acknowledged that gap and wanted to ensure that we were reporting trials in a consistent and standardised way and the common tricks that are used to distort or massage data are exposed for what they are and to assist peer reviewers in the process. Also, when things are done in a standardised way, when things are unstructured, then people will just use made-up endpoints or intermediate endpoints or whatever, and we all suffer from the lack of high-quality data.
Speaker 4:I think that companies respond to the environment they're in, and the FDA has been lowering and lowering and lowering the standard for which they will accept registration of clinical trials, and their response is well, look, it's not our job to gatekeep the evidence. Our job is to interpret the evidence. And the journals say it's not our job to gatekeep the quality of studies, it's to report the studies that were done. And then ethics committees say it's not our job to gatekeep and everyone says it's not my job and it ends up being no one's job. We end up being in a very low standard. So I think the answer to it is that it's everyone's job to make sure we have high quality evidence, and having some standards around that will be very helpful, is very helpful.
Speaker 2:So you agree with the move, then, to mandate the use of these frameworks in the design? Yes, I do.
Speaker 4:Actually, craig, I really do strongly endorse mandatory reporting. We've got some standards, like you know mandatory use of consult diagrams for randomized studies, for example, when you're dealing with indigenous data. These days we have something called the Consider Statement, which is developed in New Zealand by New Zealand indigenous authors, which is a really useful way of looking at that. Having frameworks and structures, I think, is critical, and having agreed standards is actually very helpful for the community. The risk becomes a bit like guidelines, and then that is what if conflicts of interest permeate the standard writers, and so we have to be pretty careful about that.
Speaker 3:And I think maybe the unintended consequence of some of these guidelines is they can be exclusionary by requiring a lot of resource-intense reporting and data collecting in a framework that maybe doesn't exist outside a very wealthy space. So that's just something that I think maybe people have to think about very carefully when they're authoring, but one of the papers that I'm presenting falls into very naughty reporting, which I will leak shortly.
Speaker 2:One of the interesting things in this updated guideline is to include information about in the design process how the community or how people with lived experience are actually involved in the design of the study. So that's a really interesting twist and you know, in the past I think the medical community and sponsors have perhaps been a bit fearful about that involvement but I think that we've learned to understand that that can actually make the studies much more robust and common sense and practical real world once they've actually conducted.
Speaker 4:Common sense oncology has also drafted a patient values and principles for conduct and design of clinical trials, and one of the major values that we've got at the front of that, craig, is that patients must be involved in the determination of inception and design as well as conduct. And that's because how do you know that your study is actually going to answer a question that matters to patients and people with lived experience without actually asking? And so I think it is important that people with lived experience, without actually asking, yeah, and so I think it is important that people with lived experience are involved. That's easier in some tumor types than others. You know, for example, pancreas cancer, which has got a very high mortality, is quite hard to engage people with lived experience, for example. So that is difficult, but it doesn't necessarily have to be tumor specific.
Speaker 2:I would suppose, kate, I think you've got a couple of quick bites.
Speaker 3:I do. We all love a guideline and I want to draw your attention to the recently updated Fertility Preservation in People with Cancer guideline, published in March. I think of this year Very thorough, very useful to remember that all people deserve a conversation about their fertility alongside a conversation about their cancer treatment. Get across it, as the Australians would say.
Speaker 2:Yeah, I did see that, Kate, and thought about putting on something. Glad you chose that. Was there anything particularly new or was it really just a summary of the current literature and a reminder that we should have those discussions?
Speaker 3:Look, I think it's useful in that it has a lovely title with the method of particularly for women, the method of fertility preservation, the clinical pregnancy rate expected, the live birth rate expected, the miscarriage rate expected, so you could have an informed conversation with somebody. But this is effectively a second FSA, a first specialist assessment. This takes a lot of time and we're lucky enough in Wellington to have a couple of really interested fertility clinicians who will have this conversation for us. But this is a useful base to start having those conversations. The other one that is coming, because I've just been asked to submit on it, is the cancer in those who are pregnant, which I think is going to be really, really interesting when that comes out. They're asking some really in-depth uh questions, which I thought was really cool.
Speaker 3:The other quick paper, the one that's naughty there, is the pamera. So pamera is that you um, keep somebody on palbocyclob after progression but change the hormonal therapy. It done work. It was never gonna work. I don't know why the fuck we decided this was a good idea, but anyway it doesn't work, so stop doing it if anyone's doing that, don't that harks back to the days of bevacizumab, beyond progressive progression.
Speaker 3:Drive speed nuts, anyway. And then my last paper is the long-term data, the final overall survival from Falcon, which is for Vestrant versus anastrozole. Look for, vestrant is a fantastic drug, except for the fact that it is IM intramuscular and if it had been invented before aromatase inhibitors and tamoxifen, everybody would be using it left, right, centre. But we're not. The final OS is women, particularly those that do not have visceral disease, who have metastatic ER-positive breast cancer, do very well on either indication. But listen to this very naughty and this is why I want to draw your attention to it. Among patients with non-visceral disease, a trend towards a 15% reduction in the relative risk of death with fulvestrant versus anastrozole. Median OS 65 months versus 48 months in brackets. Hazard ratio 0.85. Confidence until 0.6 to 1.2. That's in the abstract. So I think they need to read a consort.
Speaker 2:They do, or common sense. Chris, did you have any?
Speaker 4:I had a couple of wee quickies again to try and respond to my challenge, craig, not to resort to GI Wink. The wee quickies, hang on, hang on, hang on.
Speaker 2:Is that a brand of biscuits?
Speaker 4:Quick bites. It's like snacks, like canapes. We call them the canapes of oncology. So one of the papers I wanted to cover very briefly was a paper from Harvard, from the Journal of Oncology Practice, just from a month or two ago, which just looked at the patient and caregiver experience with hope and prognostic uncertainty in immune therapy.
Speaker 4:Now I think this is an incredibly difficult clinical scenario where you have people who have, for example, advanced melanoma, who have a PD-1 inhibitor which occasionally cures them. For most people it remains palliative, so it's life-altering, so it can cause temporary tumour response. In many people it doesn't work at all. But what people often hear is the potential cure in that situation and these are people often who've got heavy disease burden whatever, and we've all seen the miracles. We've got anchoring biases towards the fact that sometimes patients are cured and of course it's painful to talk to people about the fact they've got incurable disease. So what do you do? Oftentimes the temptation is to talk up their work of cure in that situation. So I find this a challenging situation a drug which has got occasional cure, but usual palliation. And how do you frame that conversation?
Speaker 4:Well, this particular study interviewed 42 patients and 10 caregivers who were receiving immune therapy, either for non-small cell lung cancer or melanoma, who were receiving immune therapy, and the melanoma could be either adjuvant or curative intent. Now they found four fascinating themes, the first of which I think is the most important one for this, and that is that the oncology team shaped the patient's hopeful expectations of immune therapy as a potential cure. So most of their excess hope is actually coming from the clinicians. So even in the Google era of medicine, they're still getting their hopes and expectations shaped by the clinical team. So it remains our job to ensure that we communicate that well.
Speaker 4:And then, unsurprisingly, that followed on from that distress related to prognostic uncertainty, particularly amongst those who experience toxicity. So once patients get toxicity, they find that very distressing when they come off the immune therapy, particularly if they think it's a curative intent drug. And then when they do progress patients that inevitably progress in more than two-thirds of people on melanoma therapies they experience quote-unquote overwhelming disappointment as well. So we're doing a lot of emotional harm to people by the way in which we frame the discussions. We have to, I think, do more work in how we frame our discussions in this group of patients who are facing this very difficult conundrum between occasional cure but usual palliation and how we do that. Well, so we have two wise oncologists on the call, and also me. So, craig, in these contexts where you have that kind of prognostic uncertainty, what methods do you use to convey that type of uncertainty to people in that context?
Speaker 2:That's a really deep question. There's this landmark paper called Hope and Optimism in a Randomized Trial of Chemotherapy for Metastatic Colon Cancer, with co-authors Craig Underhill, tim Price, neil Tebber, nick Pavlakis, michael Jappert and others.
Speaker 2:Yeah, so it is a really difficult space. Many oncologists would probably tend to overestimate benefits and give people false hope, but there is an association between hope, optimism and then anxiety and depression, and so it is that balanced conversation. I think it's a really difficult space. I'm not sure how to answer your question directly with what tools I would use. Was that what you asked me, chris?
Speaker 4:Yeah, what's your clinical approach in that situation where you hear the occasional patient cure and you've got those anecdotes of extraordinary outcomes, and how you balance that hope against the reality? For most people remains incurable. Yeah.
Speaker 2:I think you just have to have an honest conversation and you need to be careful in the use of the language and you need to talk about absolute benefits rather than relative benefits, which I think confuses people, and make it very clear that you're trying to control and slow down the cancer and not aim for cure in the palliative setting. Kate.
Speaker 3:I think things have got more complicated with that dangle, because when we were just having the good responders and the poor responders, you could always say I'm not going to make this cancer go away, but we're going to buy some good quality time, and that's really a straightforward sentence. I do like the work that Belinda Keely and Martin Stockler have done about best case scenario, worst case scenario, usual scenario and at which time point we will know what your trajectory is, so that people can plan. I think that's probably the best framework I've seen. I don't know if anybody's seen anything that's easier than that.
Speaker 4:That's the one I use, kate. It's one of the tips medical students good case, bad case, typical case. The problem is, I think, that people's understanding of their outcome changes over time and sometimes what you think you say and what people hear are different. And so, checking in with people regularly about what they understand their prognosis to be I mean, other studies demonstrate that even when you tell people they're being treated with non-curative intent, that after a while a not insignificant proportion think they're curable, you know. So people's understanding of their prognosis changes over time. And once you know that data, it suggests that it's mandatory on us to re-check in with patients about their understanding on a semi-regular basis, which, again, as I say, it's an uncomfortable thing to, but the data says that it's important.
Speaker 3:In the right patient. It can. Actually it can be done in a gentle way. You know, just check it in. You know I have a couple of hilarious, particularly men patients, so I'm like, yep, just so, you know, you still die, but not today, you know. So it doesn't all have to be doom and gloom and it's about building that longitudinal relationship, which is why we wanted to be medical oncologists, because you get to own your patients and build that relationship.
Speaker 4:You know, and and yeah, well, perhaps not own them, but they have a long quite the right way long term.
Speaker 4:And I think you're absolutely right case, and I think the other bit of wisdom that you just um snuck out there as well was the importance of including your personality and maintaining a rapport with people right now, understanding your relationship with them and knowing the style of communication that an individual knows and will tolerate and will feel comfortable with, and so personalising communication style with the individual, which, when you do have that long-term relationship with people, is just so much more possible. And it goes to show again and again and again that oncology is not a transaction, it's a relationship, and that is the beauty of the profession.
Speaker 2:Okay, chris.
Speaker 4:Yeah, look, I've got so many quick bites, craig, just so many and so many non-GI quick bites as well. I mean I do read about something other than cold long catch occasionally. I know you don't believe me, but I'll save them all up for next time.
Speaker 2:Oh, okay, good, Can I move on to mine, please from the AACR meeting? And no, I didn't go and don't want to go to America at the moment, but there was some good stuff and maybe practice changing stuff there. Firstly, in head and neck cancer. You know we don't often have a paper on head and neck cancer on the podcast, but this was done in patients with likely advanced stage three or stage four head and neck cancer. So locally advanced stage 4 refers to when the tumor is extended out into adjacent tissues but not metastasized, and this was adding doses of pembrolizumab to standard of care. So the standard of care in these patients can be definitive chemoradiotherapy or can be some surgery and then, depending on the extent of nodal involvement or extra nodal spread, can be chemoradiotherapy or just radiotherapy subsequently. So this was adding neoadjuvant and then adjuvant doses of pembrolizumab to the standard of care. Whichever was determined by the investigators. It was a big study 363 patients was conducted from the end of 2018 to the end of 2023. This is being touted as probably the first change in standard of care for this group of patients in the last two decades and it showed an improvement in the pathological complete response rate in people who had preoperative pembrolizumab. It showed an improvement in event-free survival and also overall survival.
Speaker 2:So there was a concurrent publication in the New England Journal so we'll put a link to the abstract for that paper. So you guys probably don't treat head and neck cancer. It's very much treated by a group of multidisciplinary team. But within your centre it'd be interesting to know, to know if the drug's accessible, whether they also consider this to be a change in the standard of care. But that was very much the commentary around that paper. There was another paper. This was simultaneously published in the New England Journal. I'm going to have to practice saying this name in the New England Journal. I'm going to have to practice saying this name.
Speaker 2:This is zongurtenib in previously treated HER2 mutant non-small cell lung cancer. So that's about two to four percent of non-small cell lung cancer are HER2 mutated. This is an oral irreversible HER2 selected TK inhibitor previously shown to be efficacious in Phase 1. This was from the Phase 1B. So this is drug given 120 milligrams a day. It showed 71% of these patients had an objective response in this Phase 1B study with a median duration of response of 14 months, median progression-free survival of 12.4 months. So this is a space that's free of a standard of care, and so, while this is only a phase 1b and we'll obviously move to further studies, there's a lot of hope around the ability of this drug in the future to be you know, potentially a new practice changing treatment. So currently in the US they have the antibody drug conjugate transtuzumab-duroxacan, which was one of our previously favorite names of new drugs, but maybe that's going to be gazumped by zongertinib in this group of patients. We will wait and see.
Speaker 3:I don't treat lung and this concept of HER2 mutation as opposed to HER2 overexpression is very Lago-specific. It makes more sense to me that a tyrosine kinase inhibitor would work better than trastuzumab to ruxetan, which is a delivery mechanism, effectively, rather than an anti-HER2 agent. So where does this unpronounceable medicine?
Speaker 2:Zongotune.
Speaker 3:Yeah, where does it do? Where does it work, Zongogenib yeah where does it do?
Speaker 2:Where does it work? Well, if it's a TKI, it's probably intracellular. It's going to be the downstream pathway of the HER2 on the MAP kinase pathway, I presume.
Speaker 3:And one would assume it's mutation-specific. So it's only going to take out mutated cells.
Speaker 2:Kate, don't ask me too cleverly.
Speaker 2:Oh okay, it just says it's an oral irreversible TKI that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxic effects. And a couple more interesting things from the AACR. There's another paper. This was a KeyLink 007 tumor agnostic trial of olaparib plus pembrolizumab in homologous combination repair mutation and homologous recombination deficient positive advanced cancer. So it was a tumor agnostic study, so combining olaparib with pembrolizumab, and they broke down the results into those patients who had BRCA1 or 2 mutations or non-BRCA repair mechanism deficiencies or mutations. The results looked better in the BRCA patients, with a response rate of 36%, progression-based survival of four months, median overall survival of 14 months. So certainly looking like an active combination. So it's interesting this was done in a broad range of cancers. Interesting to see this idea of combining two different classes of agents. But obviously we need to wait for more clinical trials to see if there's a trade-off not only in cost but also extra benefit over and above treating these patients with just the Olaparib. But there's certainly a suggestion that these results are superior to the single agent drug alone.
Speaker 2:And then we haven't had a PBS update for some time so I just thought I'd mention again. This is a mutation in lung cancer and this on the PBS in Australia just recently was announced that amivantamab, avivantamab it's a bispecific antibody that targets both EGFR and MET receptors, which are often overexpressed in EGFR exon 20 insertion mutations. So this was. These are for those group of patients it's about a 12 to 14 percenter, I think, of lung cancer. So these are for those group of patients. It's about a 12 to 14 percenter, I think, of lung cancer, so not an insubstantial number of patients. And so this is giving this antibody in combination with chemotherapy the basis of a study previously published in the New England Journal in October 2023, and we'll put a link to that but that drug is now available in combination with chemotherapy for patients with advanced non-small cell lung cancer with EGFR exon 20 insertions and I'm guessing, not in New Zealand just yet.
Speaker 3:And I'm guessing, not in New Zealand just yet. No, no. By and large, targeted therapies for small populations take a very long time to make their way through our processes.
Speaker 2:Yeah, and I'm trying to think, but this is potentially the first bispecific antibody available on the PBS, certainly for solid tumours in the Australian setting. So some interesting stuff from the AACR. I also noticed in their plenary on innovations they gave a plug for teletrials, or decentralised clinical trials as they like to call it so interesting that at a plenary about medical innovations in cancer they mentioned that the telephone and Zoom calls were a mechanism and innovation to bring trials closer to home for people.
Speaker 3:Well, you know, no trial is useful unless patients can access it. So traveling is expensive.
Speaker 2:Exactly All right. Well, thanks Chris.
Speaker 4:Oh, fantastic data here. Thanks, craig, and good to see some cool stuff coming out of AACR.
Speaker 2:Thanks, Kate.
Speaker 3:No mate, wa Keep warm.
Speaker 2:Thank you, Rachel. Thanks, Tim and we'll see you all again soon.
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 Babbin signing off for the Oncology Journal Club podcast.