The OJC ASCO 2026 Special Part 1

S4E4 The Oncology Journal Club Podcast 

In this special ASCO 2026 edition of The Oncology Journal Club, Craig Underhill, Chris Jackson and Kate Clarke unpack some of the meeting’s most talked-about studies and discuss what they could mean for clinical practice.

From the PROTEUS trial in high-risk prostate cancer and promising advances in RET fusion-positive lung cancer, to a rare sarcoma study demonstrating the potential of CDK4 inhibition, the team explores the data behind the headlines and highlights the challenges of translating trial results into real-world care.

The episode also dives into what many are calling the breakthrough study of the meeting – the RESOLUTE-302 trial of daraxonrasib in previously treated pancreatic cancer. With a striking overall survival benefit in a disease that has seen few meaningful advances, the results sparked excitement throughout the oncology community.

Along the way, the panel reflects on the atmosphere at ASCO, emerging trends in precision oncology, and how new therapeutic approaches such as KRAS inhibitors, bispecific antibodies and antibody-drug conjugates are reshaping the future of cancer treatment.

The Oncology Journal Club Podcast is hosted by Professor Craig Underhill, Dr Kate Clarke and Professor Chris Jackson, and proudly produced by The Oncology Network

Visit oncologynetwork.com.au for Show Notes, to send us Voice Notes and more information. And to download your bingo card if you'd like to play along with the team!

Transcript

Welcome And What’s Ahead

SPEAKER_01 0:00

Hello and welcome to the Oncology Journal Club Podcast, where Oncology Papers meet real-world practice. I'm your producer Rachel Babbin, and joining me again are Professor Craig Underhill, Dr. Kate Clark, and Professor Christopher Jackson. Together they dive into the research shaping cancer care. The important, the intriguing, and the sometimes controversial. This podcast is proudly produced by the Oncology Network. Head over to OncologyNetwork.com.au for the show notes with links to all of the papers discussed today. Okay, over to you, Craig.

SPEAKER_04 0:34

G'day,

ASCO Atmosphere And Travel Friction

SPEAKER_04 0:35

g'day, g'day. How exciting. It's Ascot time. And this is the first of two planned Asco updates. Uh, and it's a pleasure to have here Dr. Kate Clark, Hiora, and Professor Chris Jackson, who both went to Asco this year. How was the vibe?

SPEAKER_02 1:00

We're both like, what can we say?

SPEAKER_04 1:04

Were you just telling me that people are apologizing for Trump?

SPEAKER_02 1:08

Yeah, yeah. I think people are appalled at the concept of an MMA fight celebrating the 250 years of one of our greatest democracies. But as always, Chicago's beautiful. The people are so incredibly polite. Uh entry and exit to the States is is intimidating, particularly when you don't have to hand your passport over anymore because your photo recognises you. That kind of grossed me out. But no, no, and and still ASCA is an amazing meeting. The corridors are less full. Yeah. Uh definitely the planes are less full. And quite a few of the uh presenters had to be online as they couldn't get into the country, which is which is sad.

SPEAKER_04 1:44

Whoa, so tell me about that. Do you mean they're from countries where there's travel bans and so they're allowed to give online talks or so I don't think this is quite as c as as straight cut as countries' travel bans.

SPEAKER_02 1:56

No, so the two that I'm thinking of, one was from Kenya and a couple were from China. And I think some of it is just the sheer weight of numbers and not being able to turn that around very fast in a public service that over the last few years has not necessarily got a salary all the time. So I think some of it is just inefficiencies in a pr in a stressed system rather than than political disasters. Yeah.

SPEAKER_00 2:17

But also I think there were certainly uh the fewest Kiwis who've ever been to an ESCO in my memory anyway. There was maybe only about 10 or 12 possibly at the outside attending ESCO. There's normally 30 or 40, really. Uh so it was a really, really low number from New Zealand too. People are choosing to watch it online or just not going.

SPEAKER_04 2:35

So that's really interesting, isn't it? Because there was a big bounce back after COVID, big numbers, but it's dropped off again, do you think?

SPEAKER_00 2:43

Yeah, it feels it feels like it's dropped off a wee bit, Craig. You know, it's we'll I guess we'll see the final numbers uh there. Also, the pharmaceutical industry is shrinking, so there's no pharmaceutical reps from New Zealand there at all. And I didn't bump into too many Aussies either. So it'd be interesting to know how many Aussies were actually there.

SPEAKER_04 2:57

Yeah. I didn't get the feeling that there was as many colleagues going this year as other years. And maybe that's the cost as well now with the war in Iran. You know, the affairs of spite, whether that is an issue. Anyway, interesting. So, Christopher, what did you think was your highlight?

SPEAKER_00 3:15

Look,

Meeting Highlights And The Access Message

SPEAKER_00 3:16

the highlight for me was I actually got to give a talk this year. I've never done a talk at ESCO before, so that was actually the uh highlight for me. You've got a trumpet that you can blow for me, Craig. Um that was in the um in ESCO educational session for our Common Sense Oncology group. Uh look, there were a couple of highlights for me. First of all, the one of the highlights was the um president of ESCO, Eric Small, just gave one of the best oratories, presidential oratories I think I've ever heard. It was um humane, uh, it was compassionate, it was focused on community, and the theme was around uh access. Eric uh told a bit of a personal story. He lost his wife, who was a medical oncologist to cancer uh about six months ago, uh, and he shared that with the entire um audience uh ESCO, and he was just reflecting on the fact that she was a medical oncologist too. And despite all of their uh combined knowledge, uh connections, literacy, uh, and financial means, just how hard they found navigating that pathway because she had Clear Cell ovarian a rear variant of ovarian cancer, uh, and what they learnt about that from navigating the system and reflected on if it was hard for them, how much harder was it for the average person? So he just uh exuded uh compassion, concern and care. Uh, but such personal trauma only six months ago to be able to share that vulnerable with that massive audience was huge. Uh so that was a massive highlight for me. Uh and in his presidential session, he gave a shout-out to my educational session, so that was a highlight. Uh and then, of course, the um the evidence, and there's only really one trial on anyone's uh lips at the moment, and that's the uh Resolute 302 that we'll talk about.

SPEAKER_04 4:43

Yep, Greg. There was another issue that you were telling me about before we started recording.

SPEAKER_00 4:50

Oh, yeah, look, I think one of the highlights of ESCO is the connections that you have um at um at ESCO every year, the people you catch up with and uh the quality of the relationships you have. And um our co-host was really struck by jet lag and terrible insomnia. Uh and so Kate went for a wander uh late one night, and I was also out for a wander after having drank too many cups of coffee. I bumped into her accidentally, uh, and we uh and we said, Well, look, it's the only place in the street we can find which is open. Maybe we should just pop in here for a cup of tea or something. So we went in, we had a cup of tea. There were some locals there, we started chatting to the locals, and then the locals sort of thrust a microphone in their mouth. And Kate is uh uh Urswell potty and knew what to do with a microphone. She started uh talking like she was um doing a podcast, but in actual fact she ended up singing a song. It was uh so but it but she just played along with the um with the Americans. She's such a good sport, you know.

SPEAKER_04 5:46

Karaoke bar, that's what you're telling us.

SPEAKER_00 5:48

Oh no, it's called a speakeasy, and it was because Kate's a podcaster, you know. They knew that she was from the world's 30th most popular one called Your Podcast. And they they basically celebrity fangled her. That was excellent. She's lucky to get out of there in one piece. In one piece.

SPEAKER_02 6:02

Particularly as the very next artist made us uh do a dance where we all ended up in a crouch and I needed assistance to get back up again. Hopefully, it was a crossfit workout. It was a it was a Sunday night karaoke bar, which I just think we need more of those. Uh Chris is right. The highlight for me, I think, has to be all of these new mechanisms that have taken my career to figure out, and we're now seeing that coming to fruition. So the very clever science, the RAS, both on RAS and downstream RAS stuff, which we'll talk about in the next uh podcast. The biospecifics, the we're at a point now where we're thinking logically about on about cancer and then figuring out what to do about it rather than just throwing some poisons at it in a different mix each time and hope we we hit a bonus. Uh Chris and I have seen that over the 20 years of our career. It's kind of awesome.

SPEAKER_00 6:51

Yeah, I really agree with that, Kate. I mean, I think we started in the chemotherapy era and then we had the monoclonal antibody era, then the precision medicine era with targeted therapies, and then we hit the I.O. era, and I think we're at the other end of the I.O. era now with Pimbolism AB and the volume ab both going off patent next year. You know, we've had the other PD1, the Me2s have come along the last couple of years, uh, but largely it's biospecifics and the T cell engages and the antibody drug conjugates now. So it's certainly a different therapeutic era for those agents now. That's what we're seeing. So it's cool to catch up with that.

SPEAKER_04 7:22

Yeah, it's exciting, isn't it? I've seen it all because when I started, there was like about two chemotherapy drugs. So, you know, it is really very different era. So let's so you you you trained with Vincent DeVita, didn't you? No. No, Danny Davida, but I don't know a Vincent DeVita. So let's get into it. So I think you're

Proteus Trial In High-Risk Prostate Cancer

SPEAKER_04 7:41

just going to go through the plenary papers to start off with and see how far we get. So uh let's do late breaking abstract one, the proteus study. This was perioperative, neoaduvent, and adjuvant, apollutamide, and androgen deprivation therapy versus placebo with radical prostatectomy in high-risk localized or locally advanced um prostate cancer. This was the final analysis of the proteus phase three study. So these this got a lot of the uh urologists very excited. I saw a headline saying that there was 10 times as many uh complete responses, pathological complete responses, which is one of the main endpoints in the trial, which was probably a little bit of a hype because it was really 1% versus 9%. So I guess it is uh 10 times, but it's a pretty low pathological response rate. And it did demonstrate an improvement in time to first subsequent therapy and event-free survival. So this trial was for men with high risk uh locally advanced localized prostate cancer. Um, and that includes uh on staging, on clinical staging um disease extending just outside of the prostate. The traditional treatment has been either radiotherapy, which is usually combined with uh perirdiotherapy, neoadjuvant and adjuvant hormones for a specified period of time, often 12 months, or radical prostatectomy. So that's been the standard of care until this trial came along, and in this trial they gave men either ADT and placebo or ADT plus apolutamide. So there was no control arm, which was the standard of care at the time the trial was written, which was just the radical prostatectomy. So they did make a change. There was a cohort of men who did receive radiotherapy alone, um, and that will be the subject of further analysis. Um, and in addition, during the time of the study, because PSMA pets were becoming standard of care for staging, they actually modified the protocol and included that. So for the first part of the study, um men would just uh staged with conventional treatment. And they could have a PSA of up to 20, which is quite high. In our modern uh management, certainly in Australia, most men have had PSA of 20. Most centres, I think, would give them a PSA pet to really look at uh whether they have some occult metastatic disease not seen on conventional therp uh conventional imaging. So it's interesting that that that changed. And I didn't see in the analysis a breakdown of the patients who were in the first cohort or in the second cohort they had PSMA PET. But nevertheless, um they did demonstrate that the men who received apollutamide um and uh ADT, both before and after the radical prostatectomy, did have uh an advantage in terms of pathological CR rate, uh metastasis-free survival, event-free survival, and time to first subsequent therapy. And that the difference there was actually 41 months versus 74 months. So quite a big difference. So I noted that uh Declan Murphy, a well-known uh urological surgeon at Peter Mac and in private in Melbourne, was the discussant and he uh believed that this was uh a new standard therapy option uh for men with high risk uh prostate cancer. I think that's probably a true statement. It it is an option, but I'd love I'm really looking forward to seeing the further analysis um of that cohort that received just the surgery to really see whether adding in these uh hormones uh uh and androgen receptor inhibitors can uh really make a difference in these men.

SPEAKER_00 11:51

So, Craig, talk me through the endpoint, the the primary endpoint, the PSMA-based metastasis-free survival.

SPEAKER_04 11:57

Yeah, well, it might not have been PSMA pet free survival, pet guided event-free survival at that in the first part of the study because the PSMA pets weren't mandatory. But the main endpoints were this uh pathological complete response rate.

SPEAKER_00 12:16

And was that validated for any clinically meaningful uh endpoints at all? You know, is that validated?

SPEAKER_04 12:22

Not particularly, not as as in some cancers, you know, it's used as a surrogate, but it's not really, I don't think there's necessarily a correlation with survival or benefit to patients. And the rate was really low. As I said, it was 1% versus 9%. So that was trumpeted as a wow, it's 10 times as high. But you know, compared to other cancers, that's a very low pathological CR rate. So you'd expect, therefore, that if there were micrometastases in 10% of people, they they responded well. But there's if there is micrometastases, then it's not going to uh be curative.

SPEAKER_00 12:59

And the metastas-free survival, I mean the the five-year metastas-free survival difference was what, five percent? Is that right?

SPEAKER_04 13:05

Was uh 20% uh reduction in the risk of metastasis occurring. And if you look at the curves compared to some of the curves we saw in some of the other uh plenary uh presentations, you can't drive a bus between those curves. It's quite uh minimal. The event-free survival curves looked more impressive in the time to first subsequent therapy, looked the most impressive of all, with a clear difference in a benefit. And so it was nearly a three-year difference in the treatment-free interval for the men receiving the combination. So that's a big gain, but it's also three years of the side effects of the ADT and the appellutamide.

SPEAKER_00 13:45

Yeah, look, I mean, I I I I just I really worry about that because in a clinical trial where you're looking at an event-free survival on a radiologic endpoint, you're scanning people a whole lot more commonly than you would do in routine clinical practice. So the idea of initiation of your next treatment is somehow skewed by your intensity of your scanning frequency. So I don't know that that would necessarily be what would happen in in the clinic. I do worry about the endpoints in this trial crack.

SPEAKER_04 14:15

Yeah, good. And same thoughts I think that other people had, Chris. And one of the key pieces of data to come is the quality of life data. Yeah. So that wasn't presented. And so if you're going to be on treatment for an extra three years, uh, that's likely to have significant impact on quality of life. So we'll wait and see for the more detail in the subsequent presentations.

SPEAKER_00 14:38

And and I'm not a geo oncologist these days. Just can you give us a quick idea of what the toxicities of epilom evolution might be for those of those who don't use the drug?

SPEAKER_04 14:47

There wasn't a huge extra difference. The main one's actually a rash. So the um grade two, three rash was 5% versus less than 1% in the other patient in uh placebo patients. Everyone got ADT, so there's all the side effects of ADT, loss of libido, sexual dysfunction, etc., type fatigue, weight gain. But the extra difference in the apalutom is mostly around the the most in ebon is rash.

SPEAKER_02 15:17

The discussant made a point to say there's been no demonstrated survival advantage to um angen deprivation in this setting. And so they should have been an arm without the ADT protectors. That's where most of your tox is coming from. So yes, it's a cheap intervention, but it's a very expensive to the person intervention. And that that I understand there's no survival advantage to that in this setting. So they're curious as to why that was they had to go in because that's how the athletamide works. But it was odd.

SPEAKER_04 15:43

So they mentioned that there was a cohort that only that didn't get the ADT, that only had surgery, that they're going to use as a comparator. So I don't know if that's a sort of matched cohort or whether that was actually part of the random subsequent randomization was a little bit unclear to me. But you're absolutely right, Kate, because we need that survival data to really demonstrate and allow people to make the choice with the known extra side effects, a likely reduction in quality of life. What's the survival benefit, if any, that would allow you to choose that therapy? The paper was also concurrently published in the New England Journal of Medicine. Is that on our bingo card? That should be. And uh So we'll put a link to that as well. All right. Who's

Abemaciclib For Dedifferentiated Liposarcoma

SPEAKER_04 16:27

turned to present?

SPEAKER_02 16:29

LBA2 is sarcoma made the plenary. So that's pretty exciting. Just a bit of background for those of us, including myself, who do not treat sarcoma. So this trial was looking at a very small subset of liposarcoma, because liposarcomas go on a huge spectrum from sit around and don't do very much to grow like wildfire. The ones that grow like wildfire are called de-differentiated liposarcoma. And a patient may have many different, very much like neuroendoconsumer, a patient may have diverse disease within the one disease state. So they may have some poorly differentiated, some well differentiated, etc. So, in order to get onto this trial, you had to have demonstrated both uh pathologically and by progression within the last six months that you have a population of de-differentiated liposarcoma. It took uh a significant length of time to gather the 108 patients, there you go, that they have. So I think this is incredibly well done for a rare disease to get the number of patients. They're exploiting the fact that cyclin-dependent kinase 4, CDK4, is ubiquitously amplified in this disease. Um, and of course, those of us through the breast cancer, we're now very familiar with CDK4 and 6 inhibitors, and a bemocyclibe has more CDK4 inhibition than the others that are purchased there by laws. So that's why they chose a bemocyclib. Given at slightly higher doses than they give within breast cancer, but remember, these patients aren't also on hormonal therapy. Demonstrated statistically significant improvement in progression, free survival of 9.7 months versus placebo of one and a half months, which is the first scan. Uh, mediate overall survival not reached in the treatment arm as yet, but just over two years in the placebo arm. Crossover was mandated. Really interesting. Overall response rate after crossover was lower, as was uh medium progression free survival after crossover, probably because you're losing some patients as they develop more and more disease. But it's only a six-week difference or six weeks, maybe a month of organizing. So you've lost your patient in that three months, which I think is fascinating. So specifically significant improvement in PFS, encouraging OS trend, which I think we'll read out is positive. Well-designed trial and a rare disease was well discussed by perhaps a a a less enthusiastic discussant than the person that presented it, but you're worth listening to if you treat sarcoma. But uh sadly, I cannot see. I think this is the one abstract that doesn't appear to have a simultaneous uh publication. So if anybody can can find that for me and prove me wrong, I'd be happy to hear from you. But I think all of the others gained simultaneous uh publications.

SPEAKER_04 19:14

Yeah, thanks, Kate. I did a bit of digging around and was interested to know a bit more about this type of uh sarcoma and actually found an N NCCN uh publication from a couple of years ago, which was about updates in sarcoma, and actually mentioned the phase two studies that had happened uh with the CD in K46 inhibitors with this de differentiated liposarcoma. So this was probably not a surprise. It was um something that was kind of expected might be in advance. And it just to me it sort of highlights that this precision medicine, testing all tumours with next generation sequencing if it's available, looking for potential targets and then rational design of studies to prove that various molecules may or may not work in a particular cancer. I think um it's another reason why the field's moving in the way it is towards more precision medicine.

SPEAKER_00 20:12

Just a quick point on the uh common sense oncology principles here. Uh this is a trial whereby uh crossover was permitted um after progression, uh, and that did look to maintain the OS signal, even though the crossover was permitted, which suggests that the sequencing is quite critical there. So getting at first seems to be important. And those who've got their uh OJC bingo cards um out at the moment, it was a trend towards the difference, but was not totally significant, but was probably clearly meaningful. So there we go, another point for your bingo card. Fantastic.

How To Suggest Papers And Claim CME

SPEAKER_01 20:44

Before we get back to the papers, if there's a study you think we should be covering on the Oncology Journal Club podcast, feel free to send it our way. You can join the Oncology Network. Remember, registration is free, and leave us a voice note on the OJC page. That's at oncology network.com.au. Or come and chat with us on our socials. And physicians, please don't forget that you can claim CME points for listening to the show. All right, back to the journal club.

SPEAKER_04 21:15

Kate,

Adjuvant Selpercatinib In RET Fusion NSCLC

SPEAKER_04 21:16

I think you're gonna do th number three. We fought over who would do this one. Yes.

SPEAKER_02 21:21

Yeah, so Craig is not only uh involved in the in the setup thereof of this trial within his community, but he is a lung treater and I am not, but I grabbed this one. So this is LBA3, cell percatinib in early stage ret fusion positive non-small cell lung cancer, uh, and adjuvant TKIs and lung cancer. We're now up to quite a few. So we have uh osimerginib in the EGFR uh mutant space, five year OS of 85 versus 73%. We have electronib in the alk positive space, uh, four year OS of 98 versus 92%. So there's you know definitely a signal here. And particularly Particularly for both osteanidin and electroda decrease in in CNS events, which of course is symptomatically very meaningful for patients. So this setting, phase three, look, I don't I don't know why, and I'm not clever enough to understand why, so I apologize in advance. But stage two or stage one B, two or three A patients were included. But the primary endpoint is event-free survival in stage two or three A disease. There's not very many 1B patients included, uh, and they did do a secondary endpoint that attacks the stage 1B onto the bigger group. They didn't independently publish that, the what happened to the 1B group. So it kind of feels like trying to get your outcome, but maybe you'll be able to sell a bit more drug if the 1B doesn't dilute the effect of everybody else. But anyway, that's just me being acidic. So the event free survival at two years is 94% with salpacatenib and 70% with placebo with a hazard ratio of 0.17. Just remembering that the median progression free survival in metastatic ret fusion salpacatenib is about 26 months. So it's a little bit early to see whether we're just treating subclinical disease, but obviously we've seen this in OC an electinib that eventually in OS was read out. So librito 432, screamingly positive for an event-free survival. In terms of toxicity, what you'd expect are transient transaminases, all of the deaths on trial were in the placebo group, all due to disease, which is not unexpected.

SPEAKER_04 23:27

Yeah, so hopefully that if you look at the CORVs, there's again there's a big separation. So hopefully, like we saw, as you said, in the EGFR positive and alcohol positive patient subgroups that we'll see that translate into big benefits in overall survival. It's early days yet. But with lung cancer being a relatively common cancer, there's probably more ret fusion uh positive patients and some other rare cancers. Um it's kudos to Elo Lilly who persevered to get this study up and running. Um, and it's similar to the SARC 041 trial uh that you just talked about, Kate. You know, these are hard to do trials in rare cancers. So Elo Lilly came to Australia looking for centres for that study, and not one single centre in Australia was willing to take that on uh because they um they wanted two patients in the two years and uh people did the maths and they didn't think they would have enough patients. So they approached our little old regional trials network of seven sites and said, What do you guys think? We in your catchment, you've got close to a couple of million people and 10,000 new patients a year. We've worked out that you'll have more than two rep fusion uh positive lung cancer patients. Would you like to run it as a decentralized clinical trial across your network? And a few of our sites took that on. We had used a rapid start-up process. Um, so the sites went part of the governance and ethics process and then only went went did site training if they identified a patient. And um the network put three patients on within the two years. It was a global effort to get, I can't remember how many patients were on the trial cade a couple of hundred.

SPEAKER_02 25:23

151.

SPEAKER_04 25:24

Yeah, there you go. And you know, there was multiple sites across the globe needed to do that.

SPEAKER_02 25:31

Practically, Craig, so while this trial was running or routinely, you were doing ret fusions on all of your receptive cancers or yeah, so thanks to the work of Toga.

SPEAKER_04 25:41

Yeah, they were trumpeting every patient should have the next gen sequencing up front. Uh and that they've got another trial um doing that. So basically doing the patient people have enough tissue, and if they don't have enough tissue, thinking about liquid biopsies to to look to do their uh next generation sequencing, look for actionable mutations and then being able to plug them into clinical trials. So it just highlights again operationally, um, we need to put the systems in place that as many people as possible can get access to that testing, either NGSs or a panel up front, um, and then put on to clinical trials. The good thing is this is adjuvant. So this was people who'd had surgery, that's why it's the one B to three AK. The three Bs and Fours are three Bs will generally have chemoradiotherapy and the fours are metastatic. So I meant that they had tissue at time of surgery. There was enough tissue to test and there was time to process that and then put them on an adjuvant study postdoc.

SPEAKER_02 26:48

It's the one Bs I'm offended by, not the twos and threes. The one Bs are included in the inclusion, but not analysed at the end. But that's going to come out again shortly.

SPEAKER_00 26:58

Well, I think again, Craig, well done to um your decentralized trial network for participating in that to make it happen. I completely agree with your analysis that it's hard to do those trials like that of very rare mutations, but great to set actually achieved. So next time someone says it's a rare tumor can't be done, I'll say Craig Underhill says it can.

SPEAKER_04 27:15

That's right. We need to get to national studies in these rare cancers. So someone's a primary site, there's satellite sites, and they get opened if they identify the patient. Otherwise, the trials just won't get done.

SPEAKER_02 27:26

And again, I think that speaks to layers of things in the way that we conduct trials that need to change. Not every investigator needs to do 12 hours of training. I think we we have to be sensible about what we're doing here and how we're doing it. So that's I'm excited for you, Craig, in terms of the fact that you're able to make that happen.

SPEAKER_04 27:43

It's awesome. Yeah. Thanks, Kay. And big shout out to the investigators in Bendigo and Ballarat who um recruited patients. I think there was a patient referred from Adelaide for the study. I think one of the big Melbourne centres who will remain nameless who declined the study referred a patient to one of the regional hospitals to recruit onto the trial. All right. And the next one's lung cancer, so I'll whiz through that. And this is

Harmony 6 And Limits Of Trial Generalisation

SPEAKER_04 28:08

Harmony Six. So this was ivoneschemab plus chemotherapy versus tissillismab plus chemotherapy in previously untreated events squamous on cell lung cancer. This is the overall survival results of the phase three harmony six trial. I think we talked about harmony six early results, maybe in the post-ISMO. And so this the ivoneschemab is a combined PD1 and VEGF inhibitor. So this study showed after a median follow-up of 21.36 months to be precise, the median overall survival was 27.89 versus 23.69. So it's an additional four months across all the key subgroups. There was benefit in favour of the ivoniscumab group. And the presenter and the abstract said this was showed manageable toxicity because there was literally 63% of patients had a grade three toxicity, which essentially means hospitalization, and there was a 3% uh mortality rate, which was similar in both arms. So you can imagine what the with the VEGF inhibitors and lung cancer being there before. So the main uh toxicities were related to hemorrhage, homoptosis, uh, etc., and other vascular events. So it looks like a clear benefit, but uh we wait to see what the quality of life cost-benefit analysis is, cost of this drug to add an additional uh four months. But in the discussion, they did mention that this is probably the first trial in lung cancer of a in certainly in squamous cell lung cancer with a median survival of over two years. We're used to seeing median survivals of 12 months, not two years uh in these patients. But both arms did very well with just under two years uh in the arm that received chemo plus the PD1 inhibitor.

SPEAKER_02 30:15

One interesting thing said by many a discussant at this ESCO, which I think we're gonna have to get our head around, so the FDA will not approve drugs that haven't got Americans in the trial. That has filtered through to the discussants who will say this trial that is only relevant to Chinese people, for example. The more relevant subgroup who aren't involved in this trial is women, because Chinese women don't smoke. So there's almost no females in this trial at all. A woman and a man are quite a lot more different than a Chinese person and an American person. So I've I found that fascinating. The other thing I think that if we start thinking about using this combination ourselves, is the inclusion criteria is very tight to try and avoid massive hemorrhage. So they're very clear about which patients should be on trial or which ones shouldn't be. And you know there will be patient leakage because there always is. And I just think that's something we have to think about really, really carefully when you when putting people onto this red this tight region.

SPEAKER_04 31:15

So is that actually an FDA regulation? They have to be centers in America recruiting to the trial for it, or is that just an implicit bias in their approval process?

SPEAKER_02 31:26

I'm not sure if it's written down in that way. It's definitely a policy that was brought up a couple of times in the meeting. And obviously the universe is changing at the moment in more of that direction.

SPEAKER_04 31:35

So we saved the best to last.

Resolute 302 And A Pancreatic Cancer Leap

SPEAKER_04 31:37

We've got Professor Jackson put his hand up to tell us about some boring, unimportant, non-historical study in pancreas cancer.

SPEAKER_00 31:47

Well, I think if anyone's not heard the results of this study, they've um been off the grid, frankly. Um, and I think we're just going to really recap and talk talk about some of the methodological issues and some of the impact and the like of the study, I reckon. So this is uh Resolute 302. So regular listeners will know that we talked about the uh single arm study uh recently, which was just uh looking at single arm activity in a basket study, and they read out the pancreas uh I think that was in the last episode, was it?

SPEAKER_04 32:14

It wasn't it. Regular listeners.

SPEAKER_00 32:18

And we talked about the mechanism of action, which is really well worth listening to as well. So this was Resolute 302 directs on RASIB and previously treated metastatic prost uh pancreatic cancer, not prostate cancer, pancreatic cancer. Um Resolute 302 was an international open labeled phase three trial comparing oral directs on RASIB uh against dealers' choice chemotherapy in patients with previously treated metastatic pancreas cancer. Randomization one to one, more than 90% had KRAS G12 mutant disease. The co-primary endpoints were OS and PFS in the KRAS G12 population, with key secondary endpoints being OS PFS response rate and patient recorded reported outcomes in the overall population. Crossover was not permitted. We'll discuss that in the discussion. What do they find? Well, the headline result is extraordinary. Median overall survival doubled, chemotherapy 6.6 months, directs on RASIB 13.2 months, hazard ratio 0.4. It was powered for a hazard ratio of about 0.8. Uh PFS also improved 3.5 months with chemo to 7.3 with directs on RACIB, and response rates improved as well. Uh and in a disease where second-line studies often deliver weeks rather than months of benefit. Anyone remember a lotanib? Uh, a 6.6 month absolute survival gain is genuinely remarkable. Um, what about toxicity? Well, toxicity story is interesting because it's very different from chemo. Directs on RASIB replaces cytopenias and neuropathy with largely dermatological EGFR-based toxicity because this is a RAS inhibitor. Uh so RASH uh was 86% overall, which is quite high, eh? 86% uh overall RASH grade four, 14% was grade three, stomatitis 53% overall, 12% grade three, diarrhea 58% overall, which is quite a lot. Uh 5% grade 3, so less than capsidabine. And you use paranoia like in the EGFR inhibitors criticism. Strangely, that's my next point. Parinichea, 17%, essentially absent on the chemo. Um I didn't know you were gonna say that. You must have read my show notes. Uh, and dry skin 13 versus 2%. Um ration nail toxicity are highly reminiscent of EGFR inhibition, and anyone who's used cituxamab will know all about that. Uh this is a figure that um I mentioned in last week's potty, uh, and this is the fact of fatigue. Now, I will continue to maintain for many years to come that fatigue is one of the most important uh quality of life issues for people with advanced cancer, and fatigue was 23% with directs on RACIB, playing 44% with chemo, so lower fatigue, and I think that's really meaningful. Um grade three fatigue was 3.7 versus 5.6. Treatment discontinuation due to toxicity was dramatically lower, 1% with directs on RACIB, 11.2% with chemo, despite the fact they were on direction recib for longer, almost twice as long. One treatment-related grade five event, none with chemo. So they're the headline results, eh? Um more efficacy and uh swapping up skin toxicity, lower fatigue rates, for neuropathy fatigue with chemo. So let's just go through this with a CSO lens. For starters, this is a good risk population. All patients with E. cog Norton 1. Now, people who treat pancreas cancer know that a lot of people with pancreas cancer have E cog two. And this was all E-Cog Norton 1. Next of all, um, about a third of the patients in the study had undergone previous pancreatic resection. And again, people who treat pancreas cancer will know that less than one in five people has a resection for pancreas cancer. So this is a good risk group. So that's more than most metastatic pancreatic cancer studies. In addition, mandatory molecular profile and tissue acquisition probably also ruled out the rapid progresses as well in the second line study. So again, it was selecting for people who had a better overall prognosis. But that applies equally to both arms, right? Applies equally to both arms. So it's meaning the directs on RACIB are still salvaging those people whom have a delay and who progress in that time. None of that invalidates the results, but it does make the translation to everyday practice slightly less straightforward. And I think that the real-world impacts will be less than what we're seeing in the study in the second line setting. Uh now, what about the endpoints, Craig? I was giving you um a bit of a grilling about the endpoints um earlier. This is the co-primary endpoint of overall survival and progression-free survival. I don't get why they made that decision. But why was overall survival not the primary endpoint? I mean, you've got pancreas cancer, second line, it doesn't take you very long for events to accrue. And if you have a PFS gain with no OS gain, then second line, it's meaningless. So the only endpoint that matters in uh end stage pancreas cancer is OS. So why they had a co-primary, I don't know. Uh I don't understand that. Anyway, I think that's the biggest methodological criticism. Attrition before uh treatment, one notable imbalance deserves attention. Uh, 3% of patients randomized to direct on REST have never started treatment. In contrast, 15% of patients assigned to chemo never received a single dose. Now that matters more for PFS than OES. But with an OSM point, uh, those people would have nicked off and got an on-res inhibitor somewhere else or another trial somewhere else, probably. But when you've got overall survival, that's going to bias it against the um survival for directs on RESIB rather than the other way round. Uh, because it would matter for informative sensoring for progression-free survival again, which is why I think PFS is a dumb endpoint for a study like this.

SPEAKER_04 37:32

That's probably not going to explain all the difference though, was it? Because you could drive through those curves.

SPEAKER_00 37:37

100%. I mean, these are all very minor methodological points, but they do highlight the bigger picture. Uh, if it was a tighter result, but again, the early dropout, early discontinuation would inflate your PFS. It wouldn't inflate your OS. So I again think that's why PFS is a daft endpoint in a study like this. Um, so anyway, the fact that OS is so robust makes it less of a concern. Patients did not get crossover. I I celebrate that, actually, Craig, I celebrate that because there are studies where the investigational agent is actively worse. And unless you can guarantee that the investigational agent is not actively worse, which you can't in the first randomized comparison of the agent, then crossover should not be permitted. In this setting now, where you've proved overall survival, when they do it in the first line, crossover should be mandatory because at that point in time you've already proven overall survival. So for this one, I think it's absolutely the right call. It's hard to do that, uh, and it breaks investigators' hearts when you talk about there being no crossover because everyone's excited about the mechanism. But it's scientifically, it's the most rigorous thing to do. Uh, and well done to the investigators for doing that. I I really think that's uh a strength of it. So the bottom line is I think this is one of the most impressive positive studies in pancreas cancer in um any of our lifetimes. And that was uh chat, certainly in our chat groups as well. The survival benefit is large, it's clinically meaningful. You can't unpick it uh as a statistical artifact because it's real. Uh the toxicity profile is EGFR driven, but uh one that we're familiar with. And I think the fatigue is favourable, and I think that's really, really good. The key discussion discussion points aren't whether trial's positive, it clearly is, but rather how representative the patient population is of routine practice and whether it will translate, the same benefits will translate into real world practice. Whether PFS was necessary, I don't think it is, and how much confidence we have that these results will generalize to less fit patients. Now, I'm hopeful that they will. We know with BRAF inhibitors in uh BREF driver mutation melanoma that you can give them to an ECOG PS4 patient and they still work. Um, it's just how long they last for, uh, which is there. So uh I think this is the major breakthrough of the meeting. It's the major breakthrough in pancreas cancer in our lifetime. Everyone's gonna be doing me too on RAS inhibitor drugs um for the foreseeable future, and we're gonna be seeing in a first-line study in no time. Uh, and then the other question, of course, is whether it's gonna couple up with um with chemotherapy.

SPEAKER_04 40:06

Uh so there's a first-line study already underway. I think we learned about that when there was the press release. Um, we talked about that in the last episode. So I'm pretty sure when I dug around, there's already uh uh study recruiting.

SPEAKER_00 40:19

Um flicked up a trial uh sheet of all the different studies, all the different companies which were doing them uh at the moment, and it was uh you know like a 20-agent grid of studies there.

SPEAKER_04 40:30

With this particular agent, the Doroxon Rasinib, was it how do you with that?

SPEAKER_00 40:36

Directs on Rasib.

SPEAKER_04 40:37

Yep. There's actually, I think the study is chemo plus or minus Doroxon and Rasib. Uh and uh you can only imagine if that big benefit in the second line, you would hope there would be even more impressive benefit in the in the first line setting. And maybe the study needs to be just this drug versus chemo.

SPEAKER_00 40:56

I think that will probably be the next one, right? Fulfurinots versus another gemobraxane versus probably uh to check out um how it works, really, Craig, and then whether or not you couple it with chemo or not. I mean, I suspect that for pancreas cancer, it'd be great not to have to couple it with chemotherapy.

SPEAKER_02 41:11

If you think about other disease types where we have both targeted agents and non-targeted agents, the combinations with chemotherapy, if you by virtue of doing that, then uh unable to give decent doses of either always worry me. So that's number one. I think also say if we talk about breast cancer or EGFR or Razorf Wild type, colon cancer, we do our best therapy first and then use our second thing. That's what tends to work better. And so that the more targeted, less toxic therapy goes up front, and then you sage your chemotherapy to later. I don't know whether that will pan out in pancreatic cancer, and let but these people look like they may be holding on to performance status. And next episode, we will be talking about cyclic mech inhibitors, which give me even more hope. So uh in pancreatic cancer. So I think there's a lot coming.

SPEAKER_03 41:58

Great. Chris, uh, did you there was another thing we wanted to talk about.

Standing Ovations Plus Ethics And Access

SPEAKER_03 42:03

You have a little sound.

SPEAKER_00 42:05

Oh yeah. Uh I have not been in a meeting uh with a response like this before.

SPEAKER_04 42:18

But the minute I think there was not one but three standing emotions during the presentation, and the presenter complained that his time was being to by the crowd. You felt quite emotional, and I get that.

SPEAKER_02 42:29

Yep.

SPEAKER_04 42:30

I've sort of in two minds about the sort of euphoric response because again, I remain aware and respectful of the patients who went on the control arm and didn't get a crossover.

SPEAKER_02 42:42

Um but does it so but that that's where my hope comes from, because what was making me emotional was I could name them, less them, the young people that I've lost this year. And by young, I mean people in their early 30s who for six months good quality time is all they wanted. Yeah. A young man who didn't survive to his own wedding. I know in in you know, breast cancer, we're talking about 10 years, 15 years of having medicine disease. We're nowhere near that in pancreatic cancer. So the concept of six months of extra time, that's where I'm excited about. I got excited about Plferodox, for goodness sake. So, you know, so this is just a whole other thing. And as I say, I've I've got a lot of hope for their psycho mechanism. So that's where my emotion came from. And I can actually, I could picture the people in my head who I would have loved to been able to give this. Now, the sad thing, of course, is we don't know whether this is going to be accessible, both in terms of uh supply and import and cost, but at least we know the science works, and hopefully we'll we'll get some meter generics in about 25 years' time.

SPEAKER_04 43:38

No, it's exciting that's just mentioned there's a whole lot of other uh drugs being developed, but it's a small company uh developing it, so you do worry about the supply and their ability to ramp up production. But yeah, it's an amazing study and it's offering great hope. And of course, there's other cancer. That are KRAS predominant lung cancer, for example, we see we've got 12C and 12D inhibitors, but they're a minority of the KRAS, which is 30%, I think, of lung cancer. So, you know, hugely comprehensive. Colonel 40%. Yeah. Exactly. So let's hope that we see these classes of drugs have a big impact in space of time.

SPEAKER_00 44:27

So this is things are going to be ESMO, metatudiclinical benefit, four or five drugs. And clinical trials, by and large, reach about 5% of people. So we can't say that ME Too trials are the methods of accessing these because tissue requirements, because screening, because performance status, because comorbidity, because whatever. I mean, they have to be reimbursed, which means that the pricing of them has to be affordable in a single payer system. So funded by a PBS or a Pharmac. And so there is a price point issue that has to happen. But this is where I would say let's not fund the ESMO MCBS one and two drugs in order to create the money for drugs like this to actually work.

SPEAKER_02 45:09

Just a very quick shout out. In the May New England Journal of Medicine that had the phase one V2 paper in, there is a very well-written two-page article by Channing Dur and Gen Jen Ye, which explain the mechanism of these medicines. So to the trainees and non-trainees, science behind the study editorial advances in RAIS therapeutics with pancreatic cancer, get on it, and then those conversations will make much more sense to you.

SPEAKER_04 45:33

Thanks,

Reading List And Closing Wrap

SPEAKER_04 45:34

Kate. And I forgot to mention uh when I was talking about the Proteus study, there was an excellent New England Journal editorial which goes through the kind of recent history of treating men with high risk prostate cancer. So again, uh I would encourage people to have a look at that. It's not a very long one and it's very well written and uh puts this study in perspective. So we'll put a link to that as well. So lots to learn. It was a really fantastic Ascow plenary because often they have like a negative study, and it's like, why was this a plenary? Uh it sounded like it was a very exciting meeting. Um, and so we'll talk more next time. We'll do a bit of a cook's tour through, unfortunately, not through the Chicago food landscape, which is fantastic, but a cook's tour of various cancers from the Asco meeting.

SPEAKER_00 46:22

My favourite meal this year was at a Chinese hot pot restaurant with Kate, and it was really good.

SPEAKER_04 46:27

Pre- or post karaoke.

SPEAKER_00 46:29

I was I karaoke was an accident.

SPEAKER_02 46:35

The best bit about the hot pot restaurant was everybody got their own apron.

SPEAKER_00 46:42

Save my white shirt.

SPEAKER_04 46:43

Sounds intriguing. Thanks to both of you. It was very informative. Thanks to all our listeners. Thanks to Rachel on the desk there, our producer. And shout out to Graham, who's gonna splice all that and make try and make sense in the episode. So we will talk to you all again very soon.

SPEAKER_01 47:03

That's it for this episode of the Oncology Journal Club podcast, where Oncology Papers meet real world practice. If you'd like to explore the papers we discussed today, head to oncology network.com.au and visit the Oncology Journal Club tab where you'll find show notes, links to the research, and a growing collection of OJC resources. Don't forget to join the Oncology Network, it's free. You can send us voice notes and chat with us on social media. And physicians, you can also claim CME points for listening to this show. This podcast was proudly produced by the Oncology Network. Until next time, thanks for listening.