ASCO 2025

ASCO 2025: Highlights and analysis

Assoc Prof Bishal Gyawali - Queen's University, Kingston, Canada

Hi and welcome to this ecancer highlights and analysis video from ASCO 2025. We have Professor Bishal Gyawali here joining us to discuss the highlights, thank you very much for joining us.

Thank you very much for having me. It’s a pleasure to be here. I’ve realised that this is my eighth year of doing this round-up video for ecancer, I started in 2017 I guess. So it’s a pleasure.

Let’s start with the updates from GI cancer.

This ASCO annual meeting almost felt like ASCO GI, which is good for me because I treat GI cancers. There were several practice-changing trials related to GI cancers that were presented at this year’s meeting but one in particular that I want to highlight is a fancy new drug that actually improves outcomes, it’s called exercise-imumab. I’m just making a joke. What I’m trying to say is there is this trial called the CHALLENGE trial which randomised patients with high-risk stage 2 and stage 3 colon cancer after their surgery and adjuvant chemotherapy to receive a structured exercise training programme versus in the control arm where they just gave health promotion materials and told them the benefits of exercise but they did not actually have a trainer.

It sounds like a simple intervention but if you look at the magnitude of benefit this simple intervention achieved… So this was done over three years, patients received structured exercise and training for three years and this simple intervention improved the 5-year DFS rates by 6.4%, 8-year overall survival rates by 7.1%. The hazard ratio for benefit in overall survival was 0.63. These are amazing results and these are results that we don’t even see with drugs. We have not seen these results with drugs in this setting. So this is clearly a practice-changing trial.

The reason I joke that this is called exercise-imumab is if this was a drug it would be in all the clinical practice guidelines tomorrow and all the payers would start paying thousands and thousands of dollars for this drug from tomorrow. But this is not a drug so health systems actually need to invest in this because the magnitude of benefit is clearly, clearly practice changing. You are improving survival by 7.1% in a setting where people used to talk about trade-off decisions with adjuvant chemotherapy for a 5% improvement in DFS, for a 3% improvement in DFS. Here we are talking about a 7% improvement in 8-year survival rates. So I’m not exaggerating that if this was a drug health systems would have been happy to pay $20,000 a month per patient for this intervention but this is not a drug. And the best thing is it’s not expensive. I think they calculated that over the course of three years, this was done mainly in Canada and Australia, over the course of three years all the cost related with paying the trainer and doing the exercise or whatever it entailed, it cost only about $3,000-5,000 over the course of three years as opposed to paying $10,000-20,000 a month for similar, or even less than this, gains.

So this should clearly be practice changing but the thing is how do we implement this? How do health systems? Because it needs structural change – health systems need to integrate the physical training programme into their mechanism and start funding these things. And there are other benefits that you would expect from being a part of such training as well, beyond just… It’s fantastic that we have survival gains and DFS gains but there also other benefits of this. An interesting point I want to highlight is some people would think that this is probably related to weight loss but there was actually no difference in the two groups with regards to weight so the mechanism is not from weight loss alone. So this is not about losing weight, this is actual benefits of being physically active and there could be several mechanisms by which exercise could lead to improvement in survival or disease free survival outcomes. But those mechanisms actually don’t matter – why do we even care how it is working? The simple fact that it works is and should be practice changing. So I wanted to give a special shout-out for this CHALLENGE trial, it is published in The New England Journal of Medicine simultaneously as well.

But after that let’s go to one more trial from colorectal cancer, also in the same setting of adjuvant therapy for patients who have received surgery. This is called the DYNAMIC trial which is a trial of circulating tumour DNA informed treatment. Now, what do we mean by that is they measured ctDNA levels and if ctDNA is negative then it’s supposed to be a good prognostic marker. But this particular result was about patients with ctDNA positive findings and for patients who had ctDNA positive, it was a very small trial, they randomised these patients to get either the standard chemo, whatever they were planning to get, or an escalated treatment. So that means if they were planning to get FOLFOX then now they would be getting FOLFOXIRI instead, like FOLFOX plus irinotecan, or if they were planning to get 5FU alone now they would be getting FOLFOX, so an escalated therapy.

Surprisingly for some, but unsurprisingly for me, that strategy did not improve outcomes. So the 3-year relapse free survival rate, for FOLFOXIRI it was not better than that for FOLFOX or CAPOX. There are two things to this, one is irinotecan, we know that it’s not a good drug in the adjuvant setting anyway. But the most important thing is people are confusing predictive biomarker and prognostic biomarker here. ctDNA is a prognostic biomarker, that means you will always want to have negative ctDNA  rather than having a positive ctDNA. Yes, if you have positive ctDNA your risk of relapse is higher, your risk of dying is higher, but that makes it a prognostic marker. It is not necessarily a predictive biomarker. That means changing treatment based on ctDNA results may not necessarily lead to an improvement in outcomes and this is something that we should be very cognizant about because people are measuring ctDNA and doing liquid biopsies right, left and centre for every cancer nowadays. It is important to study them but should we change our treatment plan based on those results? That we don’t know yet and that is something that we need to study carefully in every setting. Like in this setting if we had not studied then we would have been misled because people do change their practice off-label, sometimes they say, ‘Oh, the ctDNA is positive so we need to give more intense treatment.’ No, ctDNA positive means, yes, the risk of relapse is higher, yes, that does not necessarily mean that we need to escalate treatment because escalating treatment might not improve outcomes. That person might relapse nevertheless or there can be so many other factors. So this was a very informing trial in that just because the risk of relapse is high does not always mean you have to escalate your treatment strategy.

We talked about predictive and prognostic biomarker, let’s talk about BRAF as a marker as well in colorectal cancer. It used to be considered… it is a prognostic marker, patients with BRAF positive metastatic colorectal cancer do quite poorly compared to BRAF negative patients. But we have now results from the BREAKWATER trial that was presented and it now confirms that it can also be a predictive marker. It has always been a prognostic marker but now it can also be viewed as a predictive marker because for BRAF positive patients with metastatic colorectal cancer they randomised patients to get either FOLFOX plus/minus bevacizumab, the standard control, versus FOLFOX plus the BRAF-directed treatment which in this case was  encorafenib plus cetuximab.

So they improved overall survival by almost double, 30 months versus 15 months, a hazard ratio of 0.49. These are excellent results and I think this should be practice changing for these bad prognosis patients. However, there are also a number of things that we need to be mindful of: a is toxicity because now we are combining everything out there together in the first-line setting so it’s going to be very toxic. FOLFOX itself has important toxicities but combining encorafenib and cetuximab on top of that. We used to do FOLFOX plus cetuximab and we are still doing FOLFOX plus cetuximab/panitumumab in colorectal cancer and that feels like the toxicities are bad but now we are also adding encorafenib on top of that so it’s going to be even worse. But the other things are about there are many patients who would want to avoid neuropathy from oxaliplatin so we also want to see the results for FOLFIRI plus this BRAF regimen, EC. We only have results from FOLFOX plus EC, we don’t have the results for FOLFIRI yet but that trial is brewing and we are looking forward to seeing that.

The other thing is about post-progression therapy. Patients in the control arm, I briefly looked at the supplement and it feels like patients in the control arm, only 16% of them received FOLFIRI subsequently. FOLFIRI is a standard treatment and I would want to see of all those patients that did get subsequent treatments the percentage of patients who get FOLFIRI should be much, much higher. The same about the percentage of patients who got BRAF-directed therapy when they progressed. At the outset the headline says that 71% of the patients in the control arm got BRAF-directed therapy at progression but that’s not actually true, it’s 71% of patients who had received any subsequent therapy which is only 61% of the patients in the control arm who had discontinued the first-line treatment. So it’s not a very high percentage of the patients who received BRAF-directed therapy subsequently. But, despite all those limitations, I think the results that we are seeing – a doubling of overall survival in these otherwise poor prognosis patients – these are impressive results.

Do you think, based on the toxicities, these results, is this going to be practice changing eventually?

Toxicity is going to be a huge limitation and the percentage of the patients who would tolerate this in the real world is going to be far less than patients who are tolerating this in the clinical trial. So management of toxicities is going to be a pretty big deal. There are so many other unanswered questions like do we need to continue this forever, can we take the chemo off after a while? Or can we at least take the oxaliplatin off? Or will the results hold the same with FOLFIRI as well? So there are several unanswered questions but I think we are going in the right direction.

Speaking of trials that improved overall survival, there was one trial in gastric cancer, DESTINY-Gastric04, which also showed overall survival benefit. This is in the second-line setting of metastatic gastric or gastroesophageal junction tumours, HER2 positive. So this is the trial of trastuzumab deruxtecan versus ramucirumab plus paclitaxel in second line. Overall survival in the control arm was 11.4 months, in the experimental arm it was 14.7 months, a small benefit but a statistically significant benefit in overall survival with a hazard ratio of 0.7.  I think the results were kind of disappointing because this drug had shown extraordinarily large benefits in breast cancer, for example, so people had high expectations of this drug in gastric cancer. It did improve survival but the magnitude of benefit was much, much more modest than what we were expecting based on its results elsewhere. But it’s good to have this option that has improved overall survival against the current standard of care.

So we are talking about gastric and gastroesophageal junction tumours but the other trials in this setting that were presented actually did not show overall survival results. The other two trials that were presented at this year’s ASCO were the CheckMate 577 trial. We knew preliminary results before as well but it stands that it does significantly improve disease free survival but does not improve overall survival in terms of statistical significance. There seems to be a good magnitude of benefit if you just look at the median but it is not statistically significant yet.

But, most importantly, if you look at the subgroup of population that has a PD-L1 of less than 1%, in that subgroup there seems to be a signal of harm. So I would say that for patients with PD-L1 less than 1% this actually should not be used. So this is in the setting of giving adjuvant nivolumab after the patients have received the CROSS regimen – neoadjuvant chemoradiation and surgery. 

But there was another trial called the MATTERHORN trial which has a slightly different treatment strategy that is perioperative chemotherapy. So a little bit of background about this is previously they used to be considered similar in terms of giving neoadjuvant chemoradiation followed by surgery versus avoiding radiation and doing perioperative chemotherapy alone for patients with oesophageal cancers. But last year we learned that this perioperative chemotherapy is probably better than neoadjuvant chemoradiation and CheckMate 577 is on the background of neoadjuvant chemoradiation but the MATTERHORN trial is on the background of perioperative FLOT chemotherapy. So what they did in MATTERHORN was for the perioperative neoadjuvant plus adjuvant FLOT they also added durvalumab to that. They found an improvement in event free survival by 9% but overall survival was not significant yet. I like that instead of just running a normal analysis they looked at the Kaplan-Meier graph and they checked that the proportional hazards were not met. So they ran a restricted mean survival time analysis as well but, yes, it has not reached statistical significance for overall survival. So I would be very interested to see how the overall survival results pan out for both CheckMate 577 and MATTERHORN with more data and more maturity. But I would say that for patients with adenocarcinoma and for patients especially with PD-L1 less than 1% then, yes, I would not be inclined to use the CheckMate 577 regimen.

Having said that, even with MATTERHORN, my concern is the adjuvant component of immunotherapy – does it actually add anything? Would neoadjuvant alone be enough? Because we have seen this in many other situations, in rectal cancer, in melanoma, in lung cancer. We have now enough evidence to show that most of the benefit is driven just by the neoadjuvant component and you probably don’t need an adjuvant component. The neoadjuvant component is given for two, three, four cycles, the adjuvant component is given for one year, so if you can avoid the adjuvant component you can avoid all the toxicities, the cost, the treatment burden, and if neoadjuvant alone is enough that would be pretty substantial savings, not just in terms of cost but also healthcare burden and also in terms of patient comfort. So one criticism of MATTERHORN or an idea for a future trial is to test for contribution of component – is the adjuvant component adding anything on top of what neoadjuvant already provides. I honestly think no, I think neoadjuvant alone should be enough, similar to what we have seen in lung cancer, melanoma and elsewhere.

Moving on to lung cancer?

No, actually I wanted to briefly talk about a trial in biliary tract cancer. It’s called the GAIN trial. I wanted to touch on this because in this trial they randomised patients to get perioperative treatment, three cycles neoadjuvant, three cycles adjuvant, versus adjuvant alone. They found that, first, very few, less than half, of the patients are able to complete the adjuvant component. Because of the massive surgery they undergo they are not fit enough to complete the adjuvant component of the treatment so many patients received neoadjuvant alone. But there was substantial benefit in overall survival here – 27.8 months versus 14.6 months with a hazard ratio of 0.46. This trial as well, other trials in aggregate they are telling us that we should probably focus more on the neoadjuvant component. The adjuvant component probably is not as important as we have been thinking so far. So I would like to see more and more trials testing neoadjuvant alone versus these perioperative strategies to see if the adjuvant component adds anything.

So what are the highlights that you’ve seen this year in lung cancer?

The lung cancer space was very interesting because there was a lot of interest from biotech companies. Lung cancer trial news were making more news in the stock markets and in the biotech world than they were making in the clinical oncology world which is interesting because the most interesting of them was the HARMONi trial of a new drug called  ivonescimab. It previously had data from China but this was a trial that attempted to prove the benefit of this drug in the broader population. In this trial almost 40% of the patients were from outside of China and this was a trial among patients with EGFR mutation positive lung cancer who had already progressed on a third generation EGFR TKI. So actually in this space we don’t have good treatment so this is a space where new treatments are needed. And it showed an impressive hazard ratio of 0.52 for progression free survival but it did not meet overall survival. In the report they say, I read the press release as well, they say overall survival has not been met yet so they are still waiting for more data, maturity of data, to test for statistical significance for overall survival.

But the interesting news in the stock market world was that the FDA has not accepted this data for approving the drug and the FDA has also asked for significance in overall survival which created lots of news because, for different reasons, I guess, a, because the FDA is now under the new administration and, b, if these results… I’m speculating of course but if these results were published last year this would have been approved immediately. So I think we are seeing some changes at the FDA and it’s a good thing that the regulators are asking for overall survival data because we have been fighting for that – you have heard me at ecancer.

Yes, I remember last year you said as well we need more consolidated results.

Yes, we need more overall survival results, we need more approvals based on overall survival. So what I’m very interested to see now is is the FDA going to apply this standard everywhere, because you are going to see lots of interesting trials from breast cancer, which we will be talking about later, and from other tumour types that do not have survival data. So I am very, very interested and intrigued to see if the FDA can insist on overall survival data for other tumour types in other settings, a, and, b, I would even go a step further and say maybe we can even look retrospectively at the drugs that have already been approved based on much, much lousier data. We have drugs that have been approved on miniscule benefit at much, much lesser quality of evidence, much, much lesser magnitude of benefit. So are we going to tackle those as well?

But these are interesting regulatory paradigms that we are eagerly looking forward to see how it all unfolds because in the lung cancer space there was one more trial – the HERTHENA-Lung02 trial for a new ADC, antibody-drug conjugate, called patritumumab deruxtecan. Even in this case OS was not met. The PFS benefit was statistically significant but it was very marginal and they even withdrew their application to the FDA. So, yes, as a researcher in regulatory policy I’m very, very interested to look at how this all unfolds but, as I said, if these were results we were discussing last year, every Tom, Dick and Harry drug would have been approved.

So, yes, definitely something to look forward to.

One more drug in lung cancer that had caught my attention but also the same problem – only PFS, no OS – was a drug called benmelstobart and it was combined with the angiogenesis inhibitor anlotinib and this was compared against pembrolizumab. I was interested because this is one of the very few first trials that have pembrolizumab as the comparator arm. Usually, I talk about this often, people keep using an inferior control arm but in this case they used pembrolizumab as the control arm which is good. This showed a PFS benefit of hazard ratio 0.7 but, again, it has to prove overall survival because PFS alone is not enough in this setting.

So what do you think of, moving on, the AMPLITUDE trial for prostate cancer?

Yes, that actually fits in very nicely with what we are talking about right now because this is a drug called niraparib which is a PARP inhibitor. This is prostate cancer and niraparib had previously been approved for castrate resistant prostate cancer, metastatic, and this trial is for castration sensitive prostate cancer. The story is the same – it improves PFS but not OS and people will claim that everybody should get this drug. But, as I said, I am very interested to see what the FDA has to say but I have always been saying that PFS is not enough in these settings. Either you have to improve survival or you have to improve quality of life.

Yes, there is toxicity to look at as well.

Absolutely, absolutely. Any time you combine a drug you are 100% adding toxicity. If you are using two drugs instead of one of course you are adding toxicity. This is the setting where you would use abiraterone alone plus ADT, of course, but here it is abiraterone plus niraparib so of course you are adding toxicity. Also for these combination regimens before being too excited about PFS we should also look at what happens to the control arm patients when they progress – do they get this drug at the time of progression? Because the answer we need is is A+B better than A followed by B. But what’s happening in many cancer drug trials is patients get A and then they don’t get B. So of course A and B both are active so patients should be getting A and B both but should they be getting it together up-front or should they get it sequentially and they still derive the same benefit? If it is sequentially then that means they will have less toxicities, they’ll have less time on an intense regimen, they will have less of all the physical, financial, time, whatever side effects that come with the combination treatments.

Speaking of PFS only, no OS trials, there were several breast cancer trials as well that fit into this category. The one that made the biggest news was probably DESTINY-Breast09. This trial compared trastuzumab deruxtecan plus pertuzumab versus the classical THP regimen, Herceptin plus pertuzumab plus Taxol for patients with HER2 positive advanced breast cancer first-line setting.  I have a special affinity with this regimen because I clearly remember when it was the CLEOPATRA trial was published I was an oncology trainee at that time and this was the biggest survival gains that I had seen during that time. Pertuzumab substantially improved overall survival, it was not PFS, pertuzumab substantially improved overall survival and there was even substantial crossover. That was a proof of test that if your drug is really good and you think that it needs to be given first line then it will improve overall survival even despite substantial crossover and you don’t need to settle for PFS.

For ten years the treatment paradigm did not change and THP continued to be the mainstay first-line treatment. In DESTINY-Breast09 it is used as the control arm, which is appropriate, and this is compared against the new regimen of trastuzumab deruxtecan plus pertuzumab. Here there is impressive PFS benefit – 41 months versus 27 months with a hazard ratio of 0.56 but, again, we don’t know what the overall survival details are going to be. This control regimen of THP when it was the experimental arm ten years ago, as I said, it has proven that if it is a good drug it will show overall survival benefit despite crossover. So for DESTINY-Breast09 as well we want to see the crossover rate, we want the patients in the control arm to get trastuzumab deruxtecan when they have progressed. PFS results are impressive and I think that most likely this will translate to overall survival results. But DESTINY-Breast09 seems to have finally changed the treatment paradigm for first-line metastatic HER2 positive breast cancer patients after more than a decade. We keep talking about drug access and PFS and waiting for OS takes time and these are legitimate concerns, but I would always support accelerated approval based on impressive PFS results like this so that patients will also start to have access. But waiting for overall survival results before making the final decision, I think that’s the right way to approach drugs with impressive benefits in PFS like this one. But we’ll see, as I said, I’m very intrigued how this new administration will look at things.

Speaking of drugs that have improved only PFS but not OS, we have a couple of them from breast cancer and these are both estrogen receptor degraders. There is a drug called vepdegestrant and this was compared against fulvestrant for patients with estrogen receptor positive, HER2 negative breast cancer after they have been on CDK4/6 inhibitor plus the hormonal therapy. The PFS in this setting was 5 months versus 2.1 months but this was only in the ESR1 mutation subgroup of patients, not in all comers. So I think ESR1 is a biomarker for this class of drugs. But there is no OS and the PFS benefit is 5 versus 2 months so I’m not impressed.

There was one more trial of sacituzumab govitecan plus pembrolizumab versus chemo plus pembrolizumab in the PD-L1 positive triple-negative breast cancer patients first line. Again, here the PFS benefit is 11.2 months versus 7.8 months, OS we don’t have the data yet so we’re still waiting for OS results. My same commentary applies to all of these drugs that have only PFS, no OS.

But one more thing to keep in mind is, especially with these combination treatments, the added toxicity, the added cost and is it justified for just delaying progression if it does not end up in an overall survival benefit. I’m also disappointed at the continuous lack of data on quality of life. I mentioned a couple of trials that did mention that but for others the quality of life data is lacking and probably they will publish it after five years. The publication of quality of life is always delayed and by that time people will have already started using the drug. But we need quality of life information to make treatment decisions today. If patients ask me, ‘OK, you are saying that it will delay progression by four months, by five months, but if it makes me feel better probably I want to take it but if it makes me feel worse I don’t want to. What do you think?’ the answer is, ‘We don’t know. They have not published the data yet for many of these.’

But there was one drug that actually improved overall survival and that was inavolisib which is a PIK3CA mutation targeted drug. In this case the overall survival was 34 months versus 27 months with a  hazard ratio of 0.67. But a couple of caveats here. One is that we need to look at what the post-protocol treatments are for the control arm patients – did they get the right treatment. Previously there have been other PIK3CA inhibitors approved in this space as well but they have not improved overall survival but this seems to be improving overall survival but sometimes that can be just a function of the control arm patients not getting the right treatment when they progress. So we need to be very careful about what the control arm patients got when they progressed.

The other thing is the overall survival as a whole, it seems a little too short. Of course, we can’t compare between trials but compared to other trials this overall survival of 27 months in the control arm, that feels very short. That’s why I am more concerned about post-protocol treatment.

Speaking about drugs that improve overall survival, there was from lung that I did not mention previously, the trial called IMforte. It’s a trial of lurbinectedin plus atezolizumab maintenance versus atezolizumab alone in extensive-stage small cell lung cancer. Small cell lung cancer is a pretty bad disease, the prognosis is around one year which is very unfortunate and we haven’t made as much progress in this space as we have made in non-small cell lung cancer. In this trial after patients received their chemotherapy patients were randomised to get atezolizumab maintenance alone versus lurbinectedin plus atezolizumab maintenance and they improved overall survival by 2.5 months, 13.2 months versus 10.6 months, which was statistically significant but it feels like a very small improvement. But, having said that, the baseline prognosis is very poor so people can argue that this is meaningful but this needs to be put in the context of, a, the increase in toxicities – the grade 3/4 treatment related adverse effects were 25.6% versus 5.8%. The other thing is the cost – these are expensive drugs. If you think about lurbinectedin plus atezolizumab and how much we pay for that and the 2½ months improvement in survival, this could be one of the most expensive treatments in terms of the value that you get from the drug when you consider a very small improvement in survival, which is there, I’m not discounting that, but the cost of lurbinectedin plus atezolizumab is going to be humongous.

I want to wrap up by tying this back to my very initial comments. This regimen will probably be approved and funded immediately and this is going to cost tens of thousands of dollars, atezolizumab alone costs $14,000-15,000 a month, lurbinectedin is going to cost another $20,000 a month to improve survival by 2½ months. But implementing exercise, which is going to cost almost nothing compared to this and will improve survival by 7%, 9%, probably that’s not going to be implemented. So that’s the paradox of our health systems.

That is very true. So once again thank you very much for doing this discussion with us, it’s always a pleasure having you. Thank you to our audience for watching this video.