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.
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The Oncology Podcast
The OJC Episode 7: ASCO 2024 Special Part 2
Discover the latest breakthroughs from ASCO 2024 with The Oncology Journal Club team!
Professor Chris Jackson, who, despite battling the infamous man flu, brings his A-game to dissect the NADINA study. Learn how neoadjuvant ipilimumab and nivolumab are transforming resectable stage 3 melanoma treatment with a remarkable 26 percentage point gain in 12-month event-free survival. Chris shines a spotlight on the innovative design of this trial and its promising implications for reducing treatment duration and financial strain.
But that's just the beginning. Dive into the long-term data from the COMBI-AD study, where we explore the enduring effects of dabrafenib and trametinib on melanoma patients with V600 mutations. We’ll unpack the nuances between V600E and V600K mutations and discuss how these findings could shift clinical practice towards more effective strategies. Plus, Dr Kate Clarke talks us through the latest on the A-BRAVE study in triple-negative breast cancer and its quest for improved disease-free survival rates.
And of course our Host Professor Craig Underhill unpacks the incredible paradigm-shifting data in lung cancer that could redefine clinical protocols. He also explores the expanding frontier of telehealth in palliative care and its game-changing potential, especially for remote communities.
Covering a whopping 17 abstracts, this second ASCO 2024 Special Episode is packed with critical insights and forward-thinking discussions that no oncology professional should miss. Join us for a thought-provoking and entertaining journey through the latest in cancer research and care.
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
Welcome to the Oncology Journal Club ASCO special episode part two. Here we take a famously different approach to oncology research. If you're looking for an enlightening and entertaining take on ASCO 2024, the OJC team has you covered with their unique blend of expert analysis and humor. Our hosts go beyond the usual presentations to highlight how the research will impact clinical practice. I'm your producer, rachel Babin from the Oncology Podcast. Joining me are our amazing hosts Professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. For additional insights and links to all the papers, visit the show notes on oncologynetworkcomau. If you or your organisation are interested in podcast sponsorship, advertising or production opportunities, please reach out to us at info at oncologynetworkcomau. This episode was proudly produced by the podcast team at the Oncology Network.
Speaker 2:G'day kia ora, kia ora. Welcome everybody to part two of the OJC covering ASCO. I know many people will have read some of the ASCO data, watched it online, been there, read the ASCO daily news or been to some post-ASCO events. Here's another digestible form, hopefully a bit of fun and education at the same time. It's a great pleasure to have Dr Kate Clark and Professor Chris Jackson, who has man flu. Thank you for joining us from your man flu hideout, chris.
Speaker 3:Do I have to cough?
Speaker 2:now to make it sound legit? Please don't, and Kate how are you going?
Speaker 4:please send cards and donations to this address look, I'm obviously brighter than chris, who is wearing a cardigan which, you know, just says everything about how he's feeling at the moment is it his cardigan?
Speaker 2:is it your cardigan, chris, or your wife's, because it's no, it's my.
Speaker 3:It's my cutty blanket. It's like my weighted ADHD blanket.
Speaker 2:There you go. Looks like you've got an animal skin or something on. All right, Chris, thanks for joining us, given you're feeling so poorly, but I think you're going to tell us a little bit about some of the melanoma papers at ASCO which were potentially practice changing at least one of them.
Speaker 3:Coming at you live from my sick couch. This special melanoma edition of OJC is brought to you by the Journal of Positive Results, the New England Journal of Medicine and the plenary session. This is an ode to why I love Australian researchers so much. Yet again, the Melanoma Institute of Australia, led by the inimitable Georgina Long, Alex Menzies and co, just again knocked it out of the park with the melanoma session. Really, the Nadina study was in the plenary, which was neoadjuvant ipinevo and resectable stage 3 melanoma. Now this of course, builds on the SWOG study previously, which was neoadjuvant pembrolizumab followed by surgery, followed by adjuvant pembrolizumab, compared to adjuvant pembrolizumab alone in stage 3, which showed an improvement in disease-free survival. This was a, in my opinion, better study of neoadjuvant ipinevo compared to surgery followed by adjuvant chemotherapy. So this study, again led by Georgina and the team, randomized phase 3 study in patients with resectable stage three melanoma to receive two cycles of Pnevo followed by surgery, followed by adjuvant IO. And the interesting thing was what they did was they did a pathological assessment as well. And if you had minimal response, then if you're a RAF mutant, you would then go on to a BRAF inhibitor and if you're a RAF wild type, you continue with the adjuvant therapy of immune therapy. So what it's kind of doing is it's taking us forward imperfectly, it's thinking what would I want to do, what do I think is the right thing to do biologically, and then designing a trial to test it. So a couple of leaps of faith, very ambitious and very exciting.
Speaker 3:So they classified the responses by pathology. Major pathologic response was less than 10%. Residual disease, PR and non-PRs went into BRAF or Advent Nivo. Primary endpoint was event-free survival, which was a time to recurrence, progression or death. This was an early report of the data but it's still pretty damn impressive. The median duration of follow-up in the study was 10.6 months, which compares to the 14 months reported in SWOC. So both are very early studies and the overall gain in terms of 12-month event-free survival was a 26 percentage point gain in 12-month event-free survival from 57% with the adjuvant strategy to 83.7% with the neoadjuvant strategy. Now this is stage 3 disease with palpal lymph node, which has a very high relapse rate at one year, and adding 23% gain with the neoadjuvant approach is just excellent to 26% and that does beat what they got with 23% in the SWOG study. One of the interesting points about this was that with their criteria for major pathologic response. 59% of patients did not need to go on to adjuvant therapy. So, from a health economic perspective, giving the six weeks of new adjuvant therapy meant that 60% did not need to have adjuvant, which cuts down the length of treatment, the exposure to adverse events and the financial toxicity of this regime considerably.
Speaker 3:There's just so much to like about this study. It's using a rational design, it's courageous, it's saying this is what I would like to do and it's taking a couple of leaps of faith along the way as well and taking us forward two steps at a time. Of course, in the adjuvant setting we want to see overall survival. That's absolutely what we want to see. We don't even have OS for immune therapy yet, and yet they designed the study to take us further on again. So the improvements in EFS are exciting. I think they will influence and change practice. Are they definitive? No. Do we need longer follow-up? Yes. Do I want to see more follow-up? Absolutely. But is this a major step forward in our field? 100%, and congratulations to the authors.
Speaker 2:Yeah, good on you, chris. So just to clarify on the IPI, it was just two doses before and was there any given after?
Speaker 3:So no post-operative IPI. So it was two cycles of Neutron IPI at fixed dose of 80. So what we would call IPI light or IPI 1 mg per kg. They've gone for fixed dosing, now IPI 80 milligrams and NEVO 240 milligrams every three weeks or two cycles, followed by a standard post-operative NEVO for the remainder of the 12-month period. So that's only six weeks of neoadjuvant therapy to get a major pathologic response in 40% of patients.
Speaker 2:Did all the patients have surgery, or if they'd had a fantastic clinical response, did they?
Speaker 3:They were all planned to have surgery, craig. That was part of the plan and they wanted to do that because of the pathological assessment, which, again, is excellent. The advantages of this compared to the SWOG study was the SWOG didn't have the pathologic assessment, they didn't have the de-escalation strategy and they didn't have the rational switch to B-REF if you've got a poor pathologic response. So I think all of those were the leaps of faith that these investigators took because it feels like they would be the right things to do, and with that approach they got the gain in EFS, which I think was great, great Kate.
Speaker 4:I just wanted to stress again that those that got a major pathological response, so had less than 10% viable tumor, did not get any more therapy. So for 60% of patients it was six weeks and stop. And people will argue, I think, about non-operative strategies and things, and I suspect that Chris may be presenting another trial for melanoma, where that is now a thing. But in other disease types we haven't been as brave. We say, oh, PCR gives you a fantastic outcome, whoever you get there 97% EFS and breast cancer but we should give people another 12 months of therapy. So I think this is very brave and I do hope they get proven right in the long term. Really exciting and, for those of us who live on the poorer side of the Tasman, much more affordable than 12 months of therapy for everybody.
Speaker 3:The other really commendable thing about the study as well was that they did mandate the pathological assessment and did that properly, because what that means is that informs your practice for later. So I don't think you can legitimately go to a non-operative strategy until you've made the step first, and this is an essential step before we can go down that road of non-operative management. So again, just fantastic. I've just got to love those Australian researchers.
Speaker 2:Thanks, chris, good on you. And so what else have you got in melanoma?
Speaker 3:There was the EBIN study, e-b-i-n study, which is BRAF induction versus going straight to IO in people with metastatic melanoma. So this is, of course, the debate that we don't know the answer to, or haven't known the answer to, which is in BRAF mutants. Do you go to BRAF-directed therapy first or do you go to immunotherapy first? We have got the SECOMBIT and the DREAM-SEQ study already, and the theory is that if you give BRAF induction you might actually exhaust the T-cells and make subsequent immune therapy a bit more useless. So it has been a bit of an open question and this study was designed to fill in a bit more of a blank. In particular, the study pre-specified patients according to LDH status LDH greater than two times up limit normal and they did a post hoc analysis too, looking at any particular features clinical features that might suggest who did better. The interesting thing about this was no major difference in outcomes between those who got BRAF induction versus those who got straight onto immune therapy, so no major differences in overall survival, which is pretty similar to what they've shown in Cicombit and DreamSeek. But what they did find was that for those who had LDH greater than two times upper limit normal, the hazard ratio favoured BRAF induction and those with liver metastases. In a post-ox and not pre-specified analysis exploratory, those who had liver metastases seems to benefit more by a BRAF induction strategy, and the thought around that is that the liver apparently surveils for T-cells and gobbles them up, and so if you've got liver metastases it makes IO that little bit less effective.
Speaker 3:Another interesting speculative question which many of us have considered before is that number of sites of disease is thought to be a poor prognostic sign for response to IO. So should you be stratifying RAF versus IO based on sites of disease? And this did not find that to be the case. And the other question which has been mooted is does the overall tumor burden in bi-dimensional measurements make a difference? And they did a cut point of 10 centimeters of some of the longitudinal diameters of tumours and they found that 10 centimetres or more was not a predictive factor favouring one strategy or the other. So it's just LDH and possibly liver mets which will need to be validated in another study indicating that some subpopulations may benefit from RAF induction. Of course, in clinical practice we've got those patients who are already on steroids where that's a straightaway. They'll go to RAF therapy if they're on steroids anyway, but it does give a hint if you've got a high LDH, maybe you should be doing some BRAF induction first.
Speaker 2:Okay, what else?
Speaker 4:Can I ask a question, chris? I don't treat melanoma, but if you do a BRAF induction and then get somebody on IO, if the cancer escapes the immunotherapy control, do you reintroduce the BRAF, do you give it another go, or that's?
Speaker 3:it? Yes, yes, yes. So if it's an induction period, so if they progress on it, you know it's not clear if, on progression, if you retest retreat, it doesn't seem to make much of a difference. But if you do the induction period followed by IO and they progressed in the study, they did reinduce the BRAF therapy.
Speaker 4:And do you know what the chances of a response are at that setting? I don't recall, kate, I'd have to look that up, I'm sorry. Look, intermittent targeted therapy fascinates me across the board, and the other thing that fascinates me is this concept of the liver being immune. Cold or immune, what's the word they use? Desert, yeah, and we see this in other disease types. There's an immunotherapy agent being explored at the moment. It starts with B, someone will remember, in colorectal cancer. That seems to work in PMMR patients, but not if they have liver mets. You know there's really interesting stuff going on about understanding seed versus soil or host versus cancer. I think you know, really, really interesting. So thank you, chris.
Speaker 3:Keep chugging Great, okay. And the last one I had in the melanoma section was a 10-year follow-up for COMBI-AD. Now this has just come out in the New England Journal of Medicine today as well. So everyone will know that COMBI-AD is the adjuvant study of dabrafenib and trimethinib compared to placebo in patients with V600 mutations, so both E and K were included. We already knew that the early results did show overall survival.
Speaker 3:But the question of course with RAF targeted therapy, is it just delaying relapse and holding people or is it genuinely curing? And that has been an open question and so long-term follow-up has been critical. The COMB-AD study at ASCO gave the longest ever follow-up in an adjuvant melanoma study, provided the longest ever follow-up results for an adjuvant strategy, which is pretty impressive, and again the abstract was presented by the excellent Professor Georgina. Long Ten-year results, many 100-months follow-up, showed improvement in relapse-free survival of 15%, reduction in distant metastasis-free survival of 11% and an improvement of overall survival of 6% with a hazard ratio of 0.8. The confidence interval was 0.62 to 1.01 with a P of 0.063, which means it's not statistically significant at that point.
Speaker 3:If you like to be a pedant and in fact the discussant was a pedant and said there is no evidence of a benefit, which I think is wrong. It's just there is evidence of a benefit, it just doesn't reach the pre-specified threshold of statistical significance. When they took out and separated the V600Es and the V600Ks, the V600E result was significant with a hazard ratio of 0.75, and oddly, the V600K results had a hazard ratio of 1.95, suggesting possibly that V600Ks did a fraction worse. Either that or just the confidence interval was wide, and so there was no overall survival gain to the V600Ks. Professor Long speculated that the Ks had a higher mutational burden and therefore may be better treated with immunotherapy.
Speaker 2:Yeah, it's interesting data, chris. And is there a tail on the curve? So you know, melanoma is now not just about those improvements in survival, but really whether there's long-term cures in patients. So in that adjuvant BRAF study was there a tail?
Speaker 3:Yes, there is. I mean, I think in an adjuvant study, when you're out to 10 years, you can say that people are genuinely being cured if you've got that 6% gain Now, 6% is the same or more than we get from oxaliplatin colon cancer. It's certainly as much or more as you get in some breast cancer regimes, so I think that this should be regarded as a standard option. Interestingly though, at the time we get the 10 year data, you've now got the neoadjuvant approach in stage three, so it may well be that neoadjuvant is going to supersede this anyway, yeah, I think there's been a move away from adjuvant BRAF inhibitors in the BRAF positive patients towards giving them immunotherapy.
Speaker 2:anyway, I think the thought is that there may be more long-term cures.
Speaker 3:Which is quite remarkable because we don't actually have that data yet. There is no immunotherapy study in the adjuvant setting that has got overall survival data as yet. We've got studies of NEVO and we've got studies of PEMBRO, the ORTC study, which have got good improvements in DFS of plus 15%, about that hazard ratio 0.49 or 0.55, depending on the study but we don't have overall survival. In an adjuvant, overall survival is king and with such effective salvage therapy, given that immunotherapy is so effective in the metastatic setting for a large number of people, it's entirely plausible that salvage IO could be enough. So strictly, we've got survival data for BRAF and we do not have survival data for IO, so it's still a hunch that IO in the adjuvant setting is better. Yeah.
Speaker 4:But that's why I think the neoadjuvant trial was so clever, because a six-week test of strategy and then no more therapy for people who are going to do so. Very well, you pick out the ones who have a need for BRAF inhibition. It's so elegant, it's very elegant.
Speaker 3:Yeah, it is elegant and it's taken us further forward and it means that BRAF inhibitors are no longer consigned to the relics of history In the adjuvant setting. It's incorporating them into a paradigm in a way in which you would want to do so again just reinforces the genius of that Nadina study.
Speaker 2:Okay, kate, you sent a message this week that you had one breast to bring to the table tonight.
Speaker 4:So we all have a favourite breast. All women have a favorite breast. Look, this is actually practical.
Speaker 2:Just to explain that to people who haven't listened to the first episode. Kate's already presented the breast data from ASCO, but she remembered this week there was another one she wanted to talk about.
Speaker 4:Yeah, because, as what happens to most medical oncologists, I had a patient for whom this is relevant and I still have some questions. So this is A-Brave, which is a study of mostly 90-something percent of women were post-neoadjuvant, having had platinum taxane and an anthracycline, but with non-pathological complete response and triple negative breast cancer. So we know these women are already at very high risk of relapse, in the order of 40% to 60% depending on the amount of residual disease. They then went on to well, the original trial plan was for them to have 12 months of a Valumab, an anti-PD-L1 that we don't see a lot of in New Zealand because it's very expensive. But after the CreateX data published so for those of you who don't do, breast women whose cancer has not managed to achieve a pathological complete response after standard chemotherapy get more chemotherapy with a hazard ratio for disease-free survival of about 0.7. They integrated that into their trial. Oddly, they were recruiting at the same time as a famous neoadjuvant IO trial in breast cancer that chose not to do that. So, anyway, so they integrated.
Speaker 4:So women were then, and three quarters of women went on to have their adjuvant capecitabine and then their Evalumab. They presented their data and, interestingly, the disease-free survival difference was not statistically significant, though numerically relevant, at about 10%. The overall survival benefit and the distant disease-free survival benefit both of about 8% 9% were statistically significant and they didn't have hierarchical P problems. So I found this really interesting. This is throwing cats amongst the pigeons in terms of do we give neoadjuvant immunotherapy to everybody or reserve it only for those whose cancers don't get to a pathological complete response, which would halve the number of women exposed to IO? And this trial has presented overall survival benefit, unlike the keynote trial which apparently is coming. I heard rumors it's coming at ESMO. Bloomberg has said that it's positive, but I haven't actually got the magnitude of benefit yet.
Speaker 2:Okay, well, I'm going to change tack a little bit now, Kate. I'm just going to mention a couple of trials in palliative care. And so from the plenary at ASCO and the theme remembering the theme of ASCO was something like don't want to misquote it the science and art cancer. So this sort of fitted with getting away maybe from the science and thinking about the art of medicine. So this was a study showing that telehealth was acceptable and non-inferior to face-to-face visits for patients with non-small cell lung cancer who had an early referral to palliative care. And to contextualize this briefly, this is going back to 2010.
Speaker 2:The plenary at ASCO featured a large single institution study randomizing people to early referral to palliative care or standard of care, and it was published in the New England Journal at the same time. So it actually showed a survival advantage to the patients who'd been referred early. The hypothesis was that they were looked after better and maybe stayed on treatment a bit longer, but it was like a two and a half three month survival advantage. So if it was represented now as a drug intervention, it probably would be a plenary as well, but not only showed a survival advantage, but improved quality of life and mood, better documentation of advanced care directives less chemotherapy or other interventions within 30 days of death, less hospitalizations and ED visits and, paradoxically, more time in the hospice, which might reflect community expectations of place of death at the time. So then a disciplinary was a study looking at whether doing telehealth visits rather than face-to-face was acceptable. This was a large multi-centre study which took five years to recruit to but it basically showed which was one of the criticisms but basically showed no difference in outcomes in terms of quality of life and patient satisfaction and also some equivalence with other secondary outcomes like anxiety and depression. So that was just a little plug for the use and acceptability of telehealth, which unfortunately the support for that from a government funding level has fallen away a little bit post pandemic lockdowns but may remain a valid tool for our overstretched palliative care system because they can't always drive out to patients' homes and for our regional, remote, rural patients it may be a good, useful tool. So telehealth visit might be better than no visit at all.
Speaker 2:And then another palliative care randomized clinical trial was looking at what's called stepped palliative care versus a monthly visit. So this was pre-assigned visits every six weeks and if the quality of life measures were stable, the number of visits was downscaled and then, following a significant event such as progression, hospitalization or some other event, the frequency of visits was re-established and again showed an equivalence in terms of quality of life and reduced hospice utilization and length of stay. So two interesting papers and just by the by our cancer center was awarded a grant recently to run an intervention study in palliative care and we're actually utilizing some screening, like we do G8 scores in elderly patients, some pre-screening, like we do g8 scores in elderly patients. So actually screening patients for the need for an early referral to palliative care or not. So there's a couple of validated scoring systems that that we're going to consider and so patients will be scored the first visit with a medical oncologist and then, if they score appropriately, they're referred early to a palliative care clinic and we're going to use step care and we're going to include telehealth visits. So it sort of validated our project plan. So that was good news.
Speaker 2:Any comments on that?
Speaker 4:Yeah, look, I was curious about their model of palliative care, which was monthly patient goes to palliative care centre rather than the other way around. So our model, at least in Wellington, is palliative care center comes to patient. So I felt like there was a missing arm. So it makes sense to me that an unwell person would rather phone in or video in if their alternative is that they have to get in a car and drive for three hours. But I'm not sure if, moving from what is our standard model, particularly in the last six months of life, which is that the team come to the patient, I'm not sure that telehealth model would be preferable to that. But I totally agree with you Telehealth is better than no visit at all and many of your very remote people do not have the option of a flying palliative care service.
Speaker 2:No, that's right.
Speaker 4:Yeah, but I was fascinated by what they considered their standard model. They also had some really interesting vignettes about some of the things they found out about their patients by virtue of if you make a song and dance of a palliative care visit, where somebody has to drive the patient to the hospital, somebody has to park the car, somebody has to get in, you might have the whole family every time, whereas if it's on the video or telephone, finally, the human gets to sort of pick the time and who's in the room with them and they found out more stuff. So they actually the stories at least, and I think narrative is actually useful. I know we're talking about data today, but narratives are useful. The stories were that having that sort of added a little bit of privacy meant that people got more information in both directions, which I think was really interesting yeah, interesting and it'll be.
Speaker 2:You know, we've learned a bit about the maori population, for example, and their, some of their cultural practices and their, their wish to actually have their I'm going to say family, but that's not right. It's one which can include not direct. Is that right? We'll give you, we, their I'm going to say family, but that's not right. It's wanu, which can include not direct.
Speaker 4:Is that right? We'll give you a listen. Say just ignore how it's spelt and just say fa no.
Speaker 2:Fa no, which refers to really support crew, which can be family or others, and there's preferences often to have the whole team in the room right. So it would be interesting to replicate that kind of study in certain populations no, totally agree yeah, chris, we're going to go back to you now to do. You got a couple of quick bites in upper gi cancer, are you still? How are you going there in your man man flu cape?
Speaker 3:yeah, look, I'm barely holding in, but I do it for the love of data, I do it for the audience. They are consigned upper gi cancer to the final session of the final day this year and I think most of the people had flown out by then and you can see why they scheduled the upper GI session for the last day, given the findings of the upper GI session were largely negative. So I'm going to scoot through these fairly quickly. Abstract 4000, perioperative ipinevo in esophageal cancer. This is a randomized study between cross-style radiation or cross-plus nivolumab followed by surgery, with a second randomization to post-op ipinevo or nevo alone. And they found no increase in PFCR rates and they're still starting with a PD. So I think the endpoint was wrong. They shouldn't be using PFCR, they should be using EFS or OS for that. But nonetheless point was wrong. They shouldn't be using PCR, they should be using EFS or OS for that. But nonetheless it was a negative study.
Speaker 3:Another negative study was Renaissance FLOT5, which was looking at a population who had limited stage metastatic esophagogastric cancer so gastric cancer or GAJ carcinoma who had resectable but reasonably low volume metastatic disease. So two groups, those with rich peritoneal lymph nodes or one organ involved, up to a maximum of five other mets Krugenberg tumors, adrenal tumors, lung tumors or a distant node, for example supercleve or one bony site. So they were treating the primary tumor plus oligometastatic disease quote unquote and looked at overall survival. Now the curves crossed in this study. There was early mortality, was higher in the surgery arm, with 8% 90-day mortality and there's a 20% reoperation rate and then later on those who did have surgery did seem to do better slightly in the longer term.
Speaker 3:Now of course, when you've got non-proportional hazards, you can't do a hazard ratio. You have to do restricted mean survival time, which they didn't do. But it did show that there's a small subpopulation who does well from surgery. But actually surgery in patients with metastatic disease is hazardous, kills people and keeps people off their chemotherapy, which is the intervention which has actually given them life for longer. So I think further work needs to be done. Those with retroperitoneal disease seem to do okay. Those with peritoneal disease did worse. So we have to further categorize this before we start considering surgery for metastatic disease.
Speaker 4:Yeah, that broke my heart, that one, because I had biases in the other direction. But one of the bits that annoyed me was that the phase two wasn't as inclusive in its inclusion criteria and then they widened the inclusion criteria for the phase three. I was like, no, but also how dangerous an RPL&D is. I think of the poor outcomes associated with. Back in the day when I did testis cancer was often the RPL&D surgery. It's a tricky operation that needs to be done in the hands of experts.
Speaker 3:Yeah, indeed, the Armani study was an Italian study I love the name Armani for Italians doing the study looking at peclotexils, remsurumab, in patients with HER2-negative gastric cancer. So a switch maintenance study. Basically, people got induction Kapox or Folfox for 12 weeks and then were either switched to PRam maintenance or Folfox, capox Times maintenance. And it's an interesting idea, actually switching your active agents after a set period of time to see if making sure you get exposure to all the drugs at a newly point is going to give you a better outcome. They chose progression-free survival as their primary endpoint, which I was pretty upset about actually, because adding in additional drugs is going to prolong your PFS.
Speaker 3:It's fairly predictable and in gastric cancer I mean, come on the overall survival's under a year in the median. You don't have to have a large number of events to prove overall survival gain. In that population the median PFS was improved by three months, which is surprisingly enough about the gain you get by adding in PICC-RAM anyway. And the big issue of course, adding in Paclitaxel to Folfox is they get more neuropathy. So I don't think that's going to be a winner based on the excess in terms of neuropathy, which was 61% versus 45% worse than the PacRam arm and only a month or two different in the overall survival.
Speaker 4:We need video, Chris, of Craig's face when you said how many people got peripheral neuropathy.
Speaker 3:Yeah, video, chris, of Craig's face when you said how many people got peripheral neuropathy. Yeah, it was pretty bad. Eh, the giant study in pancreas cancer, gemabraxane versus expensive Folfuri oh, I mean nanoliposomal irinotecan with 5-FU In older patients with PDAC. That was closed for futility. I really just think that nanoliposomal irinotecan should give up. I really just think that nanoliposome or in a TCAN should give up.
Speaker 3:Then looking at another study in adjuvant pancreas cancer so adjuvant head of pancreas, so resected head of pancreas patients had induction adjuvant gemcitabine times five months, randomized to finish with gemcitabine or have consolidation chemoradiotherapy. So this is an important question. Local relapse is still an issue in head of pancreas cancer and the radiation oncologists want to muscle in in this field as often as possible. So should you just give chemo or should you give consolidation chemo radiation at the end Overall negative for overall survival. So again, no role for adjuvant radiotherapy. Maybe that's a take-home message, but there did appear to be possibly a benefit in node negative. So I'm sure the radiation oncologists will still be encouraging us to consider consolidation radiotherapy in those node-negative patients. And intuitively, node-negative patients are more likely to be a localized disease where a localized therapy like radiation might be helpful, and whereas node-positive is more likely to be a systemic disease. Maybe that's when you need to just stick with the systemic therapy. Abc07, unresectable cholangiocarcinoma again ad ABC-07, unresectable cholangiocarcinoma.
Speaker 2:Again, adjuvant chemo induction followed by either more chemo or chemo with showing FLOT was better than CROSS that. Maybe we don't need radiation oncologists at the upper GI MDTs anymore. What do you think about that?
Speaker 3:We need for you to have Kate's face reacting to that I've got a great deal of regard for a wise, thoughtful, interested radiation oncologist. I think they add enormously to the MDT. I think there's a subclone of radiation oncologists who see them as deliverers of radiation rather than physicians, and I think we should all see ourselves as physicians and contribute to the best multidisciplinary management of our patients.
Speaker 2:Yes, I agree it was being provocative, but I think it's interesting. We seem to have, at this meeting, diminished the number of patients they'll need to be involved with a little.
Speaker 3:Radiation oncologists are a resistant clone, some would say a malignant clone, but they will survive.
Speaker 4:I think there's also a huge difference between the limitations of external beam and what opportunities SBRT provides for us. We just haven't got the data yet. It's all coming. It's all coming. You know, if you can kill stuff from the outside without chopping people up, you know it's coming.
Speaker 3:Yeah, I reckon we're going to get to TNT and esophageal cancer. And you know, radiation oncology has always gotten out. Oh, you know, that was with old technology. Now we've got better techniques, we We've got better imaging. Let's give the radiation anyway. Oh, it was the wrong fractionation schedule. Oh, it was the wrong dose. There's always a doubt.
Speaker 2:Yeah, all right. So we might have left the best to last, which is the lung cancer data. So I'm just going to whiz through that. Time's marching on.
Speaker 2:But there was a couple of practice-changing papers presented. I think you know each ASCO there's sort of a different emphasis. Some years it's a GU doctors come away very happy. Or a few years ago, you know, there was some, you know it might be breast, but this year it was probably lung cancer seemed to be the tumour type with the most interest in probably practice-changing data.
Speaker 2:And so the first study was from the first day, five-year crown data showing continued benefit with lorlatinib in advanced out positive non-small cell lung cancer. This was presented by Ben Solomon from Peter McCollum Cancer Centre in Melbourne and it showed quite provocative data. There was tweets going out showing the survival curves, with people driving trucks between the survival curves, so it was really impressive data. There was tweets going out showing the survival curves with people driving trucks between the survival curves, so it was really impressive data. The medium progression-free survival was not reached with the five-year follow-up with lorlatinib, compared to nine months with crizotinib, and 92% of the patients at five years given lorlatinib were free from intracranial progression. So that's quite substantial data in this first-line metastatic setting.
Speaker 2:Of course, out positive on small cell lung cancer is about a 4% of all advanced cancers, but lung cancer being so common, it translates into a significant number of patients. With the advent of the targeted therapies, one of the take-home messages is we do need to be testing routinely in lung cancer for biomarkers and getting patients onto targeted therapy as appropriate. And then, what did you think of that data, kate? Because did you see that session?
Speaker 4:I have one absolutely glorious patient on lorlatinib, but he got his cancer at the wrong time and so he had a whole brain radiotherapy back in the day. And so, despite what I said defending radiation oncologists, we do have this window, and I've had the similar problem with melanoma patients who got their melanoma at the wrong time, got whole brain radiotherapy and then lived much longer than expected. So it's tricky when new stuff comes and you almost end up. What's the word Sisyphean something? I'm sure there's a Greek myth that fits. But I'm very excited by the fact for these patients it's a chronic illness and it's a tablet or two a day. They don't even have to go into centre. That's fantastic.
Speaker 3:What's the toxicity?
Speaker 2:like Craig, yeah, there's some specific toxicities with it, and it includes hypercholesterolemia, weight gain, which needs to be managed. Quite a significant proportion of patients need a dose reduction, and so we've talked before about those low-grade but chronic toxicities that can have an impact on patients. So it's not without its toxicity, but needs management or dose reduction.
Speaker 3:Yeah, I agree. I mean, a month worth of grade 1 toxicity can be worse than a day of grade 3 toxicity. Right, yeah, that's right. And is that the optimal agent, Craig, or are there better ones?
Speaker 2:There's some fourth. This is a third generation. There's some fourth generations coming, but this is the best one to date. So we have this available in Australia. I'm sorry, new Zealand. I did look it up. It's about $7,000 a month, but patients are able to go onto this upfront. Then the next generation of studies might be with the newer agents again, or it might be around using biomarkers or to try and de-escalate, but the thought is that people will need to be on this drug lifelong.
Speaker 3:Is osimertinib EGFR or ALK?
Speaker 2:EGFR.
Speaker 3:EGFR okay cool.
Speaker 2:But it's a very good question because the next paper is actually about osimertinib and so again, targeted therapy, and this is the Laura study, late Breaking, abstract 4. So they're just giving osimertinib after chemoradiotherapy for stage 3 patients with EGFR-positive, egfr-mutated disease. So they excluded exon-19 deletions and L858R mutations which are resistant to the osimertinib. So again, patients stayed on osi long-term. Again very impressive progression-free survival curves at 39 median progression-free survival versus 5 for the patients on placebo. So hazard ratios of 0.16. So again, quite impressive. And this is for progression-free, not overall survival. But this is a maintenance strategy in effect for stage 3 disease patients, with very few of those cured by standard chemoradiotherapy. So again, probably a change in paradigm. Now this drug is available in Australia for unresectable stage 3s, so stage 3Bs and 4s, but not as yet for the stage 3A Kate the stage 3Bs and 4s, but not as yet for the stage 3A, Kate.
Speaker 4:So do you think there will be a paradigm shift where either chemo radiotherapy falls away because it cures what did you say? I think it's about 10% of patients. Isn't it in the control arm at that point? Or do you think that the chemo radiotherapy adds something?
Speaker 2:The cure rates has been a little bit higher than that. So the discussion went over that. So in the historical arms of randomized clinical trials the chemo radiotherapy arms have been in the 20 to 30% range. In the Pacific study, which was adding dovolumab as maintenance after chemo radiotherapy, the placebo arm had a 33% five-year survival. In the DERVA arm it was 42%, just to put that in context. So we don't have the survival data yet from this Laura study, but the thought is that this data is more impressive in these patients than immunotherapy and so that's probably the paradigm shift. And again, like we saw in that crown study, the CNS protection in these patients was quite impressive. So at the CNS disease-free survival in these patients it was substantially improved. It was like a 97% control rate at three years versus 77% with the placebo arm. So again there seems to be we're basically treating people with micro-metastatic disease, so 30% might be cured long-term but 70% are going to relapse and so putting them onto osimertinib up front seems to give longer disease control but again it's a lifelong treatment.
Speaker 4:I don't think that the trialists believe that chemoradiotherapy is curative because there is no end to the osimertinib. If that was truly an adjuvant trial as opposed to a maintenance treating subclinical metastatic disease, they would have said six months, 12 months, three years, whatever. They didn't. It's until progression or until recurrence, whatever hard to judge in a post-chemoradiotherapy lung. So I'm just curious as to what the chemoradiotherapy is generally adding in this EGFR mutant population who? I think the trialists believe that stage three lung cancer, that is, egfr mutant, is not curable and I think there's going to be more stuff coming out of that.
Speaker 4:I'm curious as to the discussions that must have been had around the table. I would have loved to have been in that room when they were designing the trial, but yeah, I find that really, really interesting. I can't remember if the discussants actually released the de Valiumab broken down by EGFR because there were so few. The Pacific trial I also have to give them an up for switching from an ocean to a sea. I thought that was, you know, because you know all comers was an ocean with Pacific, and then the narrowed population was Adriatic. I quite like that.
Speaker 2:Yeah. So the take-home message is from the discussion of this study was again that the design acknowledges that very few stage three unresectable, non-small cell lung cancer patients are likely to be cured. So pragmatic design. But the next generation might be biomarkers to guide de-escalation, so there might be a subset where you don't need to continue on lifelong, Chris.
Speaker 3:Yeah, I agree, kate. You took the words right out of my mouth. This isn't an adjuvant study at all. That's the early treatment of metastatic disease, isn't it? And that's what we're seeing here, craig, what were the rates of exposure to osimertinib in patients at progression?
Speaker 2:The crossover.
Speaker 3:Yeah.
Speaker 2:It was quite high it was. I've got it here.
Speaker 4:From memory, chris, it's very high because it was in the protocol. Yeah, so they did. Actually, they do have to be given up. Yeah, it's in the trial protocol that the patients in the control arm are.
Speaker 3:So it was crossover, yeah, mandated crossover, yep.
Speaker 2:It was 81%. I just found that, and so that compared favourably to previous crossover studies in stage 4 EGFR disease.
Speaker 3:Yeah, that's a really good number. And so, craig, do you think that the DFS is enough or do you think you need OS, given that it's an early versus late study?
Speaker 2:Well, the OS is still not. It's not. There hasn't been enough events. So yeah, it would take some time. But again, I mean, we often see this, asko, don't we the discuss and saying this is immediate practice changing. So again, people were tweeting memes with trucks being driven between the curves. I think someone tweeted a giraffe in between the curves with a long neck, because it's hard to say orally to explain them, but the difference between the curves is just quite stark. At five years we've got 70% progression-free survival versus 13%. We rarely see curves like this in medical oncology. So, given that there was the crossover, you would imagine that that would water down perhaps the difference in overall survival or delay the event. So we haven't seen enough events to have the survival data as yet.
Speaker 4:So this was the argument that I had online with someone was that if now again, I don't treat lung cancer, but if giving someone osimertinib at time of recurrence salvaged everybody, then you would avoid osimertinib immediately post chemoradiotherapy and that might be a good thing. Or it might be that that 19% who don't get the osimertinib at recurrence or relapse or whatever we're calling it, because they are too unwell to and they're missing out on therapy, and that bit matters. So I do think there's still questions about this. I think that, absolutely, this is an effective drug which, when you give it to people, it works.
Speaker 4:But this is an early versus late study, though I did have a fight with somebody who said that it's not that you'd need to do something else to prove the answer to my question, and I didn't understand the stats. But yeah, I'm curious. I think if I were this is a bit where it's sneaky, though if I were a patient with EGFR mutant stage 3 lung cancer who had Kigame radiotherapy, I'd probably buy myself some Osimersinib. So that's where I'm very naughty. So, intellectually, I want some data.
Speaker 2:I was going to ask you the same question. You want some data. Yeah, I was going to ask you the same question. You know you apply the mum test. If it was your mum, or if it was you family member, friend, colleague, what would you do?
Speaker 3:I think it just goes to show that being alive and free of disease is important to patients yeah, yeah all right.
Speaker 2:And the third lung cancer abstract it's probably practice changing is that we're going to switch to a different c, going to adriatic C. This was late-breaking abstract number five. So this was looking at the role of davolumab consolidation in limited-stage small-cell lung cancer. So the standard of care in this has been carboplatin and toposide combination chemotherapy for several decades and this is the first time we've seen in a large randomized clinical study a new intervention that improves overall survival. Take-home messages median overall survival with Diverlamab was 55 months versus 33 months. With placebo. Progression-free survival was 16 versus 9 months. Of course we have the standard side effects of a single-agent checkpoint inhibitor to manage but again, when you see the gap between the curves it's statistically significant but also clinically meaningful I think, with at three years of 10% absolute benefit of in survival, 47 versus 57%, hazard ratios of 0.73.
Speaker 4:Yeah, I was first an oncology house surgeon in 2002, and this is the first time practice has changed in small cell lung cancer in that time. So the previous study, the osimertinib maintenance slash adjuvant, got a standing ovation. My little group near the front row of hall B1 or whatever it is forced a standing ovation for this one because nothing has changed in 20 something years. So this was really exciting.
Speaker 2:Yeah, yeah. So there you go. So probably a new treatment. It's not yet available on funded but it probably will be down the track. So not in terms of tomorrow in the clinic, not immediately practice changing, but I think with time it will All right.
Speaker 2:And then a couple of other things to mention. There was a little bit of pre-ASCO meeting hype about sasituzumab versus docetaxel in second-line treatment. Again that hype probably was downplayed during the meeting. They teased out that patients who hadn't previously responded to IO had a clinically meaningful but not statistically significant overall survival. So that was the subject of press releases. But I think the discussant really downplayed the benefit of really didn't convincingly beat standard of care which remains docetaxel or probably another clinical trial.
Speaker 2:And also again a little bit of hype about a new KRAS G12C inhibitor which is a significant proportion of lung cancer. I think it is an advanced lung cancer. It's about well, all of GKRAS is about 15% and the 12C is a significant subset of that. I can't remember the exact number off the top of my head but again this showed a small progression-free survival compared to docetaxel but didn't demonstrate convincingly a clinically meaningful survival advantage. So an expensive treatment option over docetaxel as it stands. All right, we've covered a lot of data in this episode and the last one. Any final thoughts? Kate, I was intrigued about the standing ovations. I've sort of in two minds about that Again. I guess when you haven't seen a new change and a new treatment in a particular tumor in three decades, it's easy to get excited.
Speaker 4:So the largest standing ovation was for the OSSE trial, the melanoma one didn't get one Deserved it, and you would have thought that was more practice changing. So, yeah, look, I think it very much depends on who's sitting where and if they've pre-planned it to be fair. So I think my cynical brain on and I think there were in the sessions that I went to that weren't plenary I think there were other equally worthy practice changing pieces of data, and I'm not on the organizing committee or the educational committee. They obviously have a very hard job, but yeah, I think it's very hard to pick a winner when there's probably some really other sexy stuff out there. Chris.
Speaker 3:Do you reckon they should add the amount of applause got at the plenary to the ESMO Metatronical Clinical Benefit Scale?
Speaker 2:That's a good thought, no because it's so easily gamed.
Speaker 4:You know, you just fill the what.
Speaker 3:You mean like other aspects of trial design in points, kate which are not easily gamed at all.
Speaker 4:I mean, the yucky thing for me you know I alluded to it once today already is the press releases that come via Bloomberg or Money R Us, and you often get a hint of data months before you actually see the actual data. And there was an article in the popular American press about one particular shareholder of a medicine that is not actually big names, but a medicine that had done well head to head in pretty much a me too fashion, and his share price doubled overnight and his personal wealth went into the multi-billions as a result. And that part of ASCO grosses me out.
Speaker 2:And the food's crap.
Speaker 4:Yeah, the food in the actual centre is truly awful, but Chicago's improving and there's now several mojos, which is Wellington coffee Fantastic.
Speaker 3:Well, I commit to all listeners to the OGC podcast to go and give a food review from Esco next year.
Speaker 2:Yeah, that'd be great. Now it's a bit of a foodie city. There's some great restaurants, but the food in McCormick Place is just truly woeful. So big shout out to Esco Need to do something about that, because us international travelers we're just not into hot dogs or slices of pizza and that horrible, horrible percolated coffee.
Speaker 3:They need to change the name of coffee. It's not the same drink.
Speaker 2:No, it's not, is it All right?
Speaker 3:Okay, team, I'm going to have to crawl off to my sickbed. Yeah, good on you.
Speaker 2:Chris.
Speaker 3:The toll of the recording has finally caught up with me and I need to crawl back under my covers and recover.
Speaker 2:Yeah, I hope you're feeling better soon. Thanks everybody. Thank you, rachel. Thanks to everyone who's listened. We welcome the feedback and we'll talk soon.
Speaker 4:Bye-bye.
Speaker 2:And thank you, Rachel.
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 Journal Club podcast. Proudly brought to you by the Oncology Podcast. Part of the Oncology Network For healthcare professionals. Seeking regular news updates and insightful discussions, we invite you to join our community at oncologynetworkcomau. Your free registration includes a complimentary subscription to our weekly publication, the Oncology Newsletter, a valuable resource to stay updated on the latest advancements in the field. We value your input and welcome your feedback and paper recommendations via our social media channels, email and website. Your insights help shape the conversation and drive the direction of future episodes. This is Rachel Babin signing off for the Oncology Journal Club podcast.