Please note:

GI CONNECT podcasts are designed to be heard. If you are able, we encourage you to listen to the audio, which includes emotion and emphasis that is not so easily understood from the words on the page. Transcripts are edited for readability. Please check the corresponding audio before quoting in print.

This GI CONNECT programme is supported through an independent educational grant from Bayer and is an initiative of COR2ED.

The views expressed within this podcast are the personal opinions of the authors. They do not necessarily represent the views of the author’s academic institution, or the rest of the GI CONNECT group.

Jenny Seligmann: So hello and welcome to this podcast covering lower GI highlights from ESMO 2022. I'm Dr. Jenny Seligmann and I'm a GI medical oncologist and I'm based in the University of Leeds in the United Kingdom. Today, I'm delighted to be joined on this GI CONNECT podcast by Dominik Modest. Dominik, would you like to introduce yourself?

Dominik Modest: Hello everyone. My name Dominik Modest. I'm a medical oncologist working at the Charité in Berlin, just like Jenny, on specialised treatment of colorectal cancers. I'm happy to join.

Jenny Seligmann: Great. So today we are going to review some of the key colorectal cancer abstracts from this year's ESMO meeting. And I think, Dominik, I think it's pretty fair to say that it was a really good congress for colorectal cancers. Not all congresses are.

Dominik Modest: It was. Truly.

Jenny Seligmann: It was truly a great congress for colorectal cancer. So the main topics that we're going to cover today, so we're going to cover the NICHE-2 trial and give you some context to the new saying ‘the Chalabi plot’. We're also going to look at an interesting abstract using HIPEC in locally advanced colon cancers and also look at FRESCO-2 and the emerging story in KRASG12C mutations. Shall I start with the NICHE-2 data, Dominik?

Dominik Modest: Please go ahead.

Jenny Seligmann: So the NICHE-2 trial was run in the NKI in the Netherlands. And this was building upon the NICHE-1 trial. So the whole purpose of this route of investigation was to look at the role of neoadjuvant immunotherapy in patients with locally advanced deficient mismatch repair or MSI high colon cancer - not rectal cancer, so colon cancer. And so the NICHE-1 trial really showed some early encouraging data, not just with safety, but also efficacy. So, the NICHE-2 trial built upon that to see whether the signal that had been seen in NICHE-1, which was just in 30 dMMR patients, actually could be seen in a larger population. So the trial was now over 100 patients and the co-primary endpoints were safety and feasibility and three year disease free survival. And so what was presented in the presidential symposium was safety and feasibility and the secondary endpoint of pathological response.

So number one, in terms of safety and feasibility, I think we could all be quite convinced by that. The treatment was very well tolerated and there was less than 5% grade three events, which led to almost the vast majority of patients having surgery as planned on time within a six-week window. So that was very encouraging. I think the thing that really caught everybody's attention was the waterfall plot on response. This is something that we haven't seen in colon cancer before. So Myriam Chalabi reported a major pathological response rate of over two thirds of patients. And I'm going to use the figure here of 67% of a pCR, which is incredible. Would you not agree, Dominik? I mean, the whole place just burst into a round of applause. It was phenomenal.

Dominik Modest: Really. Yeah. Never experienced something like that. And colorectal cancer. I mean, we're used to these scenarios in melanoma or other breakthrough immunologic indications, but not in colon cancer. So it was really great to see this. And also that the patients who did not have a pCR, nearly all of them still had a major pathological response. And I think the key thing about it was only three weeks of treatment. If we just imagine the time from start of this study until timely surgery was considerably short. I think during COVID we had these time intervals, maybe in the routine care without having trial therapy, and they managed to integrate that into the short term interval. So basically, it's really, really tough to find any aspects of concern to discuss on that trial, which is a really hard job for us in this podcast! I may pull up one…  Jenny, you've been heavily involved in the FOXTROT trial and I think we've been discussing the concept – or the emerging concept – of having neoadjuvant therapy in colon cancer, just like in rectal cancers over the last years. And I think one of the major issues and also aspects that were criticised heavily from surgical and also radiological societies was that pre staging is really hard in colon cancer. It's not an MRI of the pelvic region. It's hard to stage these. And I remember that the point of concern was especially MSI tumours. So having that in mind, how do you interpret the patient selection? Have they all had a tumour that was truly T4. Can we control on that? Was everybody in need of immunotherapy despite this unprecedented efficacy?

Jenny Seligmann: Yeah, I think that's some of the key questions that would come out of that. So in terms of the radiological staging, you're right, it seems to be more the nodal disease where the problem is and in MSI-high tumours. So we know that it's almost like tossing a coin in terms of calling nodes. So I'm not sure how confident you would be in their baseline radiological assessments, particularly with the N2 stage, I don't think we'll ever know the answer to that. And I think that there's a lot of work to be done in radiological staging in colon cancer. But I don’t think that that would stop delivering the whole story. I think this is going to emerge alongside the development of this whole new field, which is neoadjuvant colon cancer. And I think everyone's starting to understand that this is a field in colon cancer that we're now going to start moving to. And we need to improve the radiological staging as we're going, rather than stopping everything in its tracks because of the radiological staging. This could be done in parallel, of course Dominik, you need to then balance the risk of the treatment that you're giving versus the risk of uncertainty. And please just remember our position with adjuvant chemotherapy. We've been giving adjuvant chemotherapy - for how many years? - to a lot of patients that didn't require it. And here we've seen beautifully that this treatment is safe. So I think in turn, this is a conversation to have with the patient, but absolutely no way should that be a barrier into the progression of this extremely exciting field. So question back to you, Dominik. What would stop this being based upon the data that we have at the moment? Would you want to see disease-free survival? I mean, what do we tell our patients in clinic? Where are we going next?

Dominik Modest: Basically, I was just trying to give you a hard time in terms of finding perspectives! I think we're pretty much agreed. I think the DFS will be a challenge because as it was reported orally, there hasn't been a record of relapse yet. So I think they are on their way to have a quite convincing three year DFS rate. So basically I'm not sure whether this will change. And the median follow up, which was clearly better than the data that we had in rectal cancers at ASCO with the six months of dostarlimab, was longer than a year in contrast to 6.8 months with dostarlimab. I think the questions are quite clear. How much immunotherapy is needed for maybe those that have not reached a pCR? And the key question, of course, somehow emerging is, is that a curative therapy in itself? We cannot answer that now. I think we need the long-term follow-up data as they are now and see whether there is distant relapse. I think we are pretty much confident maybe with the rectal cancer trial to have a local control assessment and maybe extrapolate that to a certain extent to the colon where we find it increasingly difficult to monitor. So we are getting in the uncertainties here.

Jenny Seligmann: You see it as an uncertainty. I see it as opportunity. I think, number one, we can't completely extrapolate rectal to colon. I think you're right. I think we could be looking at cure in some patients, but we need to be confident that we can have a monitoring of response in the way that it's taken 20 years to get to organ preservation protocols in rectal cancer. There are none in colon cancer. Colonoscopy, of course, is going to be more difficult. Some of the flexures, you're just not going to be able to get good pictures. So yes, absolutely. But I think the next cure. Absolutely. But we need to find ways that feel safe and good ways to monitor the patients and monitor response. So I think this is, again, just opening a whole new era for personalised medicine and colon cancer, which is super exciting.

Dominik Modest: Agreeing on that, I would try to put a bit of context to emerging or maybe old stories which have a certain overlap with the NICHE trial. So I'll take a hard turn and introduce the HIPECT4 that we've also seen at ESMO. This was an oral presentation and it comes up with a quite somehow intuitive but maybe difficult question. The question of the HIPECT4 trial was in CT4 patients, so clinically T4 patients with colon carcinoma, it was randomised to do upfront surgery and adjuvant systemic therapy versus surgery plus a HIPEC with mitomycin C,  30mg per square metre over 60 minutes (to the community these details are absolutely important and this is why we mention them) followed also by adjuvant systemic chemotherapy. The primary endpoint of the trial was local relapse or local control, which was clearly demonstrated to the surprise of many colleagues. I think we can say that after many, many negative trials of HIPEC that were tested in colorectal cancer of any kind of stage and treatment situation, we also had DFS and OS, and I think it's fair to say that the initial local effect did not translate into DFS or maybe also with a small trend and absolutely not into overall survival. So basically from my point of view, we have one of the most convincing demonstrations that HIPEC does something. So there is a local effect at least on the peritoneal relapse rate. However, this is also an adjuvant therapy and I think although this is coming a bit out of the corner, I think we have to put that trial into perspective with the just discussed NICHE-2 data or what's your perspective Jenny?

Jenny Seligmann: Yeah, no, I agree. I think for these really locally advanced tumours, I mean I personally would have given them upfront systemic treatment in that situation and particularly now considering a lot of those tumours as you said were dMMR or MSI high, going straight to surgery with HIPEC is clearly not going to be the best approach. But complete kudos to the investigators. These trials are very hard to run and when the trial was set up, certainly upfront systemic treatment would not have been in their minds. But Dominik, how relevant is local control? I mean, when you think about all of the steps you need to go through to have an approved treatment in early colon cancer, should this change anyone's practice? Should we be doing this for any patients? Were there any groups that benefited more than others, do you think?

Dominik Modest: So, from today's perspective, the answer, at least my answer is clearly no. I think we miss a lot of data of that trial that we should urgently get. Most of it is dMMR or pMMR. We have not seen the data. So the key question is which proportion would have been eligible for concepts like investigated in NICHE-2. We do not have any other molecular pathology except for mucinous and signet ring cell carcinoma which I find difficult to understand why these were evaluated and MSI/MSS was not, so I think many details of that trial are still unclear and it shouldn't change our clinical practice, but it might change to some extent our perspective on HIPEC because honestly spoken when I was coming to ESMO, I did not expect this trial to show anything at all. After the experience we had with the PRODIGE trial in metastatic colorectal cancer and cytoreductive surgery, which was super negative, there was not even a small signal of anything. So basically, it does not change my clinical practice, but I think it changes my perspective on HIPEC and maybe if we are able to understand who are the like absolute 10 to 12% patients that did not relapse in the peritoneum, this may open up opportunities for the future to better select these patients. And I think we will clearly and quickly agree that this will be an MSS population or needs to be an MSS population because all the other patients also...

Jenny Seligmann: I think the other question we need to ask is can we be looking at other intraperitoneal therapies? So in ovarian cancer they do other different things. You know, there's more, rather than just one dose of HIPEC there's other methods of delivering intraperitoneal chemotherapy. Maybe if we're not seeing spectacular results with HIPEC maybe we should be continuing to think about local treatments, but maybe thinking about alternative approaches.

Dominik Modest: Okay, so we agree this does not change clinical practice. But Jenny, is there another trial that may change clinical perspective?

Jenny Seligmann: Well, I suppose the data that was most likely, I suppose, to routinely impact patient care would be the FRESCO-2 trial. So as you know, regorafenib is the only TKI which is approved in metastatic colorectal cancer. So the FRESCO trial was looking at fruquintinib, which is oral tyrosine kinase inhibitor of VEGF receptors 1, 2 and 3 and FRESCO-2 follows on from FRESCO-1, which had been run in China, which was testing fruquintinib in heavily pre-treated patients versus placebo but the need for another trial was felt that the standard of care in China in terms of a pre-treated patient was different from international practice. So hence the FRESCO-2 trial took place. So again, patients were heavily pre-treated and had to have had either regorafenib or TAS-102 and patients were randomised between fruquintinib plus best supportive care versus placebo plus best supportive care given the stage of the patient journey at that point. So overall survival was the primary endpoint and there was, as you can see, there was a significant improvement in overall survival, which was modest but arguably clinically significant within this population. The data are quite similar to what we had seen in other agents in this disease setting. There was a significant improvement of progression-free survival as well of around two months. The safety profile I thought looked reasonable. The main grade three toxicities were hand-foot syndrome and hypertension, less hand-foot arguably than regorafenib. So I think it was generally felt to be well-tolerated. So Dominik, what were your views? Does this now represent a new standard of care?

Dominik Modest: Yeah, I think so. At least a new potential standard of care. I think what I found a bit amazing in cross trial comparison is that the disease control rates, at least from my point of view, for the first time, was higher than 50% in that situation. We've never seen this with TAS-102 (trifluridine and tipiracil) however you call it and regorafenib, they never made it across this kind of landmark. So this was clearly better with fruquintinib. This is, I think, one aspect. The other aspect was the absolute gain in overall survival was, I think, a lucky measurement. So the hazard ratio and the gain in benefit I think is pretty much comparable to what we've seen with trifluridine and tipiracil. So that's basically, I would say, the same class of effects on the overall survival. With the toxicity I think you've summed it up nicely. However, it's a TKI, it's not so far away in terms of how the molecule is built from regorafenib, and I think we will figure out when we treat patients regularly on that drug. I expect a bit more side effects as we see with trifluridine and tipiracil and maybe a bit less as with regorafenib. And it might be somewhere in between these two drugs. And yeah, I think that's all set, it’s a new drug on the horizon. That's good news.

Jenny Seligmann: Yeah. I mean it's just one of those things, as we know, that's diminishing returns with each line of treatment. And so the number of patients that make it then to the position, if it moves forward in the patients who have had to have been treated with either TAS-102 or regorafenib if it's in that post progression population, I suppose the concern is there's fewer patients that are actually going to make it to that treatment line. So it'll be interesting to see where it is positioned eventually.

Dominik Modest: Yeah, I agree. I think if it needs now further development, I think to have trials in the third line setting are what is asked for, in the fifth line setting or sixth line setting as it was developed now because that was the patient population, I think the overall benefit for the whole population, I think we easily agree on this is considerably small. However, I think in that setting, going to third line, second line and also pre-treated patients, I think there's quite a lot of development. 

Also at ESMO and I think it might get into certain clash with another kind of strategy that was emerging and I'd like to introduce at this point, which is the KRASG12C mutant metastatic colorectal cancer story. We sum up two abstracts which are basically exploring the same strategy, which is the combined inhibition of the EGFR receptor with either cetuximab or panitumumab in combination with the G12C inhibitor, which was in the one trial adagrasib  and the other one sotorasib, so we have two active combinations, both were tested in pre-treated patients, heavily pre-treated patients as well, and I think the overall message was pretty simple, at least from my point of view. These combinations do work. We have a very good disease control rate, which is the vast majority of patients, above 90% in one cohort, and also objective response rates, which is beyond 30% at least, I think we can estimate from these small numbers might be even above 40% in the end. I think we have to see more patients and larger cohort to really estimate where we are. However, I think the region of objective response rate exceeds everything that we have seen as last line options, so I think there will be further development. And I think the key question, and Jenny you may comment on this, how to proceed with these combinations in the future. Where is the story leading us?

Jenny Seligmann: Sure. I mean, I think the one thing to point out is this does represent a small population of the metastatic colorectal cancer population. Excuse me if I'm wrong, off the top of my head, about 2%?

Dominik Modest: I think 3 to 4. Be a bit optimistic!

Jenny Seligmann: You're ever optimistic. Okay. So even by that, the very nature of the rare alteration does impact on the type of study design and the level of evidence that's going to be needed. I mean, it's been really nice following the story, which reminds you back to the BRAF story of the evolution of how it went. And now where we have an approved drug. Interestingly, in that setting, when we think back to the BEACON study where things have gone. So we started in the second, third line and now the interest is moving in to the first line in combination with chemotherapy. I'm very excited about seeing those patients being treated in the first line. I think you should be giving patients your most effective treatment upfront. I think we've got very good evidence that shows that depth of response to your first-line treatment has impacts all the way through. However, I suspect what we're going to end up with is a larger study again in patients who have had at least one or two lines of therapy. And it's going to really need an international effort to identify these patients and get them enrolled. And, of course, ask what the best control arm is for this group as well.

Dominik Modest: Yeah. So basically a lot of work to do. I think as you've pointed out, I think one of the major takeaways that we have is that the combined inhibition of a MAP kinase alteration together with the EGFR receptor is needed. And I would be surprised if the story would change if we get other KRAS specific inhibitors like G12D which are on the horizon. So I think for the overall strategy, how to combine drugs to find synergies, block escape mechanisms, these two abstracts were really helping us. Considering further development, I think we have to acknowledge that this is true for the BEACON as well as the now presented abstracts on G12C the efficacy of these targeted combinations is superb in terms of short term. We have super response rates and in the vast majority of patients, however, durations of response are limited. There’s evolution in the tumours ongoing and therefore I think the effort will not only be internationally in terms of how many centres that we need to recruit these patients. I also think that combinations maybe with classical chemotherapy, if you move to the first line, are needed to achieve the mentioned depth of response. Or do you have another perspective?

Jenny Seligmann: I completely agree with that. And I think unfortunately it sounds very simple, but I think even now Scott Kopetz presented more data from BEACON, again, just demonstrating the complexity with the targeted treatment. So it's not just as simple as targeting this pathway and targeting that pathway. And I think we'd be naive to go into future development thinking it's going to be quite as simple as that. So exciting times. So I think we'll sum up there. I hope you agree that this has been a really exciting time for colorectal cancer. It's been a really good conference. Thank you, Dominik, for sharing your perspectives and I hope everyone has enjoyed this GI CONNECT podcast.

Dominik Modest: Thanks a lot, Jenny. It was a pleasure.

Podcast transcript
GI CONNECT Update from ESMO 2022: upper GI cancer highlights

Please note:
GI CONNECT podcasts are designed to be heard. If you are able, we encourage you to listen to the audio, which includes emotion and emphasis that is not so easily understood from the words on the page. Transcripts are edited for readability. Please check the corresponding audio before quoting in print.
This GI CONNECT programme is supported through an independent educational grant from Bayer and is an initiative of COR2ED.
The views expressed within this podcast are the personal opinions of the authors. They do not necessarily represent the views of the author’s academic institution, or the rest of the GI CONNECT group.

Samuel Klempner
Hello and welcome to this podcast covering upper GI highlights from ESMO. I'm Sam Klempner. I'm a GI medical oncologist at Massachusetts General in Boston, and I'm joined by a good friend, Dr. Yelena Janjigian. Yelena, you want to introduce yourself quickly?

Yelena Janjigian
Yes, thanks for having me, Sam. It's a pleasure to discuss updates from ESMO 2022. It was a great Congress in Paris. We're all back reliving the meeting and so it's a perfect time to discuss what we've learned.

Samuel Klempner
Yeah, so we're going to hit the highlights. We'll talk a little bit about some frontline data and then move into the second line space. You know, I think this whole world of gastro-oesophageal cancers continues to evolve, which is a good thing for our patients. So I'm going to start off by asking you about some data that you presented which leads into maybe some bigger questions about how to move beyond your CheckMate 649 data. So, you had a nice poster from a Fellow looking at the combination of FOLFOX and PD-1 and building upon that. Do you want to talk a little bit about that?

Yelena Janjigian
Yeah, thanks. So one of my junior colleagues, Dr. Cytryn, presented - exciting opportunity for a junior, to showcase your junior faculty and fellows. This is a follow up to CheckMate 649. We know that most of our patients in first line setting derive a degree of benefit from immune checkpoint blockade. But given the fact that our tumours are chromosomal unstable and quite complicated, the tumour microenvironment needs a little bit of a boost and so that's the rationale behind many of the combination studies that are ongoing now. Our Phase 2, FOLFOX, regorafenib, nivolumab is one of them. This is building on the work showing the tumour targeting with trastuzumab for example, and anti-PD1 therapy combination may help augment the antitumour immune response. So we looked at first-line patients irrespective of PD-L1 status and assessed progression free survival and overall response rate and other markers of clinical benefit in first line setting. What's probably one of the more striking findings about the study is that the rate of PD-L1 positivity in first line setting was substantially lower than what we saw in CheckMate 649, using 28.8 antibody. Some of it is likely to be patient selection because people were probably directing a patient to a study if they were PD-L1 negative. But also, it's the difference in PD-L1 testing amongst the studies. We found that the study met its primary endpoint (6-month PFS), the progression-free
survival benchmark that we were hoping to achieve - we did. So this is again confirmatory data to consider combination strategies in first-line setting.

Samuel Klempner
Yeah, I think trying to address the potential immunomodulation of antiangiogenic therapy is definitely a strategy that has some legs in this disease. It's similar to this trial, I know you've also been involved in some of the lenvatinib studies and we've certainly seen some mixed frontline later line LEN (Lenvatinib) PEMBRO (pembrolizumab) data in the past. But we did see a little bit of an update and some clues into how this phase three regimen is going to be tolerated. I don't know if you want to give us a little highlight of the lead in from this trial?

Yelena Janjigian
Yeah. So LEAP-015 is a large Phase 3 study that's currently ongoing globally. I would say in the United States since Checkmate 649 made immunotherapy available for all, the accrual in the United States was a bit difficult because the comparator arm did not have immunotherapy. So that will make the data interpretation a bit harder once the data is available. But globally, the study had no problem accruing and in the United States we also put a few patients on mostly PD-L1 low tumours. Essentially it's the same question - will lenvatinib help move the bar above what we've accomplished with CheckMate 649? We know KEYNOTE-62 data with pembrolizumab in first-line setting initially was disappointing. We do think pembrolizumab and trastuzumab are very similar drugs, so that should not be a factor. But whether or not, you know, I mean the preliminary data presented at ESMO suggested that the combination was doable. It's tolerable. Grade 3/4 adverse events rate was, as you would expect, and it's manageable. So let's see if it's better. It’s too soon to say but certainly preliminary data suggest that it, as you said, may have some potential in subset of population.

Samuel Klempner
Do you think - just since we have you here and you sit at a position of sort of seeing the 10,000 foot view over the landscape - do you think that the patients that are going to be enrolled in these novel combination strategies are going to be pre-selected for the PD-L1 low population since we sort of have a standard? Or do you have no concerns about enrolling a PD-L1 say, CPS-high patient onto a combination since they're getting IO potentially in both arms?

Yelena Janjigian
Yeah, it's a great question. I think for the studies that have IO in both arms then the question is what's the risk to the patient and adverse event profile? And I can tell you the answer is always try to put the patient on the clinical trial. But if a trial, for example, like LEAP-015, did not have an IO in comparator arm. Our patients are quite informed and knowledgeable. And you know, as an oncologist, I wouldn't necessarily risk randomisation to a non-IO arm, particularly in patients with PD-L1 five or higher tumour. I think it's a bit of a stretch, especially in the United States where our patients don't like to be randomised to begin with. But I actually was very excited to see your updates from the DisTinGuish trial and you know, we need better biomarkers to augment the antitumor response. What is your experience with the drug and the development of this agent?

Samuel Klempner
Yeah. So as you said, it's really all about biomarkers. And I think there's a lot we still need to learn about these patients. But one strategy has certainly been trying to modulate the microenvironment towards a perhaps more favourable mix. You know, we know that a portion of these patients are enriched for myeloid derived suppressor cells and T regulatory cells and maybe
sort of reversing that immune contexture might allow for better response to checkpoint inhibition. And that's sort of the broad theory behind targeting DKK1, which is potentially a novel biomarker. Essentially patients with high DKK1 tumours seem to be enriched for some of these immunosuppressive features and associated with a worse prognosis. So there seems to be identifying a biologic subset meant some resistance to 5FU. So in the past, targeting this strategy had been done in the later line setting in combination with pembrolizumab, where looking back on the patients, the responders were heavily enriched for DKK1 high tumours. So it begged the question of could we develop a biomarker enriched strategy to potentially improve upon the outcomes? But initially this required some development in the front line. And so the DisTinGuish trial is actually now a three part study, but originally a two part study, with a front line and a later line cohorts. The front line is what was presented at ESMO. And this is a combination of 5FU platinum in this case CAPOX and a PD1 agent tislelizumab in combination with DKN-01 with the main goal of trying to, as you said, improve upon what we get for 5FU platinum and PD1 alone. And essentially out of the enrolled patients, one thing, a couple of high level highlights, the biomarker prevalence seems to be somewhere in the 40 to 50% range. So if this holds, it's, it may be relevant for a pretty large portion of our patients. And then encouragingly, in the biomarkers enriched group, the DKK1 high patients, the response rate was quite high at 90% in that subset. So we're encouraged by this, but it's relatively small numbers in non-randomised data. So what's happening now and we hope to see in the future is that there's a randomised phase two which compares 5FU platinum and tislelizumub versus 5FU platinum, tislelizumab and DKN-01 and this is exactly what you were saying. So I feel comfortable enrolling essentially all comers onto this trial because both arms are getting the IO. But I agree in non-IO containing control arms it becomes a little bit of a discussion with these very informed patients, but certainly an encouraging signal.

Yelena Janjigian
What about dual anti-PD-1, CTLA-4 blockade? You know, it's the more drugs you add, obviously there's more toxicity. We've considered using a stepwise approach, right, sequencing the drugs, which is also an interesting question to answer. We saw data from the MOONLIGHT study. What is your take on it?

Samuel Klempner
Yeah, I know you've been involved in some of the later line IPI (ipilimumab), NIVO (nivolumab) checkmate 32 data in the past. So we sort of knew what the safety and potential early efficacy markers were from this combination. And of course it was an arm in 649 as well. But the question remained is, as you mentioned, if you could do this sequentially and potentially leverage the benefit of remodelling with chemotherapy and then come in with the dual checkpoint blockade versus in a totally upfront combination way. And it's a little bit of an unfortunate result. But this was a well conducted study from the German group in a 2 to 1 randomisation of 5FU NIVO IPI all concurrently versus 5FU followed by IPI NIVO and then NIVO with IPI spaced out farther as sort of per the standard. And really what they show is that their PFS at six months was really not substantially improved. Perhaps there was some activity, you know, response rate was there and a little bit higher in the combination arm. But I think this is a tough strategy to take forward after this data and perhaps there's some subsets in there. You know, as they tried to tease apart the PD-L1 expressing patients, maybe there are some people who would do better with the dual checkpoint blockade, but it's hard to envision either of these arms going forward in large studies. And I don't know what your opinion of an upfront FOLFOX IPI NIVO triplet is, but I think that there may be are some other combinations that will rise above that.

Yelena Janjigian
Agreed. And particularly it was disappointing results for certain because you know, my inclination, interpretation of CheckMate 649 data and as you mentioned CheckMate 32 data before is that in IPI responders, patients who respond to IPI, the duration of response is quite dramatic. And so it is a worthy endeavour. But given the MOONLIGHT data and the toxicity profile and the fact that now there's newer, better CTLA-4 inhibitors that are Fc modified with less and more favourable adverse event profile, I think we're moving on from NIVO IPI to the next sort of phase of our drug development and everyone's super excited about tumour targeting and immune checkpoint blockade, but I think there is still role for immune checkpoint blockade combinations with newer inhibitors. So we'll stay tuned for the next wave of the data to read out. What about FOLFIRI based combination? What are your thoughts about that? That was another study. Certainly, you know, a little disappointing, but curious to see what you think.

Samuel Klempner
Yeah, I mean, as you well know, not everywhere around the world has equal access to frontline checkpoint inhibitors and the approvals in the EMA are slightly different than some of the other approvals globally. So there is still a portion of patients who won't get a checkpoint in the front line. So the French investigator group, which has always done very good work, essentially, were trying to ask a question in the second line setting where maybe they use a little more front line triplet with Flot, etc.. So there's a little bit more FOLFIRI. And the French have always been believers in FOLFIRI. And actually we've used FOLFIRI periodically in the second line as well, but they are essentially asking the question of FOLFIRI plus durvalumab versus, and FOLFIRI, plus DURVA (durvalumab) and TREME (tremelimumab). So, they're asking a question about second line population and combining. First, is it safe to do FOLFIRI and checkpoint inhibitor? There's not as much data there, so it's good to have data. And second, do we see a signal? So they were asking both of these arms whether or not they would improve the PFS at 4 months beyond what a sort of their target range was, 70% PFS at four months. What they did show is that actually neither arm achieved the primary goal, but they did see some, a little bit hard to interpret in sort of these data sets, but there were definitely some tails on these curves. There was an overall PFS that was at least comparable to what we've seen in second line. And there were some durable responses. But the regimen, as you suggested, with this CTLA-4 and checkpoint is not without toxicity. And there was almost a 50% rate of grade three or higher adverse events. So this is in a second line setting where we're not talking about curative intent. I think all of these things need to be weighed against the toxicity and what we may achieve with standard. But I do think there's still a role to asking questions about the later line use of checkpoint inhibitors. You know, with the increase in front line use, are there ways and strategies to consider continuing these agents potentially beyond progression and salvaging with traditional regimens or other checkpoint inhibitors or molecularly inform strategies? So it's good data to have. It's unfortunate that we didn't see more encouraging results, but I do think that the French deserve congratulations.

Yelena Janjigian
Well, you know, I think, as you alluded to, to me, it is still useful data. We knew that beating TAXEL (paclitaxel) RAM (ramucirumab) is not going to be easy, but I would say the toxicity profile is surprisingly, you know, it's not so bad. So, certainly again, second line setting is tougher, but what it gives me is some assurance. We have sometimes patients who are not platinum candidates in first line setting. Right. And so if you were to try to use immunotherapy in first line and you couldn't use FOLFOX, perhaps extrapolating from those data, you could be reassured to use it because we know FOLFOX and FOLFIRI are equivalent in some studies that we looked at from the French group. So there may be some utility for this study, even if it's not practice changing. It's good to have in your sort of slide deck to review with the fellows as they come through your clinic.

Samuel Klempner
Yeah, I completely agree. I mean, we've had a few patients, as I'm sure you have with, you know, essentially anaphylactic oxaliplatin reactions every once in a while where you really even with all the descents in the ICU, you just can't go back and use the drug. So this is definitely something that's nice to have in your back pocket to know that there's some safety data there.

Yelena Janjigian
Exactly. Or patients who are FLOT failures, for example, and recurred within six months. And you just don't want to use a platinum. But they have not had immunotherapy yet. So this is a cohort of patients that you may consider irinotecan based first line therapy. And here now you have PD-1 as at least reassuring data that you're not going to be hurting those patients because the concern is obviously for overlapping liver toxicity and so forth.

Samuel Klempner
Totally agree. And, you know, the question of toxicity is something that brings us to one of the other data presentations from ESMO, which was an update in a group of patients that I know is dear to your heart, which is the HER2 positive population. So we saw an update from DESTINY-Gastric02. Maybe you can give us the high level of the study population and the high level results?

Yelena Janjigian
Sure. You know me, I can talk about HER2 the rest of the day, but this is obviously an important patient population. Right. We knew for over a decade that HER2 is an important target, but in second line setting, many of the studies have failed. And the reason why is because it's a relatively heterogeneous disease and becomes more heterogeneous as the cancer progresses. So using antibody drug conjugate trastuzumab deruxtecan, was really successful strategy came in DESTINY-Gastric01 which was the randomised phase two study looking at T-Dxd against Investigator Choice, third line therapy. Right. This was already what led to the FDA approval of trastuzumab deruxtecan even in the United States but in other countries, in Japan. So in the United States it's approved after trastuzumab failure. So technically in second line or beyond and in Japan in third line. So that's why it was critical to have a Western experience with trastuzumab deruxtecan. And that's where a DESTINY-Gastric02 comes in. It's a single arm study, very much selective patient population where biopsies at the time of progression on trastuzumab were mandated. And this actually is in the FDA package insert of recommendation that if you can please biopsy your patients at trastuzumab progression and at ESMO, we saw updates from that data set. So basically the confirmed overall response rate is very similar to what was initially presented and published. Disease Control Rate was very favourable to what you would expect, with similar HER2 negative strategies, right. With Paclitaxel, and ramucirumab and the adverse event profile is what we see associated. I think often, we forget that this is chemotherapy, right? We're used to perhaps thinking of it as a targeted agent that is not maybe as toxic, but it's definitely a chemotherapy. It has 1:8 drug to antibody ratio so higher than many of the other ADCs. And you see bone marrow suppression, which in U.S. patients, we actually see a little less in Japanese patients because in the US it's mostly a second line study, but you see nausea and vomiting and liver dysfunction sometimes. But one of the side effects that everyone's very concerned about, particularly in second line setting, is interstitial lung disease. We don't see a particularly high rate of ILD not as high as you see perhaps in lung or breast cancer, but it is a real risk and you have to monitor your patients carefully. And so it was nice to see the Western experience updated by one of my
colleagues, Dr. Ku, who presented this data. And again, we use this drug in the clinic, standard practice now,we do biopsy at the time of trastuzumab progression and offer it to the patients and it's a great option.

Samuel Klempner
Maybe my last question for you, just practically speaking, for all the people listening, do you guys do anything special for monitoring beyond looking at ILD on the standard response assessment scans, no special interim PFTs, etc.? You know, sometimes we hear about this.

Yelena Janjigian
Yeah, and this is a very good question Sam, and comes up quite often when I speak to my colleagues and the answer is no. You have to monitor them carefully with scans. And when I say carefully, read the scan and look at the results yourself, look at the images. Because often these small ground glass specifications are not even, they don't make it into the impression. It's in the body of their read because the radiologist doesn't know what treatment the patient is on. And these GGOs may be completely insignificant in that, you know, age of COVID, where everybody has some sort of upper respiratory infection. So you have to do your own surveillance. In clinical trials such as DESTINY-Gastric03. As you know, we're taking this regimen perhaps to first line. We do recommend pulmonary function tests, but honestly, it's not a very common occurrence for ILD. So to do PFTs in clinical practice for all, it's a bit of an overkill. I think you just need to talk to your patients and monitor the scans carefully because if you stop at grade one or even possibly intermediate between grade one and two ILD. Most of these patients do just fine. There are very few, if any, grade five events. There was one grade five event, death, on DESTINY-Gastric02. It's more common in breast cancer patients because they get a lot more therapy and also many more of them have chest radiation and other factors. But in gastric, you know, you should be fine with just routine scans and just, you know, looking at the scans carefully.

Samuel Klempner
Yeah, that's been my experience as well. Well, look, this was an awesome rapid fire review. It's always great to see you and hopefully next time will be in person. So I want to thank everyone for listening and want to thank Dr. Janjigian again for giving us her time. And I look forward to talking again.

Dear colleagues. My name is Thomas Winder. I'm a Medical Oncologist from Austria.

It's an honour and privilege to present to you today the NICHE-2 trial.

The NICHE-2 trial was presented at the presidential session at the ESMO 2022 meeting.

NICHE-2 is a neo-adjuvant immunotherapy trial in locally advanced colorectal cancer patients. So, they included in the intention-to-treat analysis 112 patients.

As you are aware around 10 to 15% of patients with locally advanced colorectal cancer are mismatch repair deficient. The recurrence rate of these patients is around 20 to 40 percent with standard treatment options.

So, in the NICHE-2 trial, they treated the patients in the neo-adjuvant setting with a combined treatment of nivolumab and ipilimumab followed by a single treatment with nivolumab followed by surgery.

The primary endpoint of the study was safety and efficacy defined by pathological response.

So now I want to present you the fascinating results of the study.

The study was safe and around 98% of the patients received surgery timely. And now the intriguing results on the pathological response. 95% of patients had a major pathological response and 67% of the patients had a complete pathological response.

These are intriguing results. They also presented the disease-free survival with the median follow-up of around 13 months, and there were no recurrences.

You need to keep in mind that in this setting around 40-50% of high-risk stage 3 colorectal cancer patients recur with standard treatment options. So, these results are really fascinating and potentially practice changing.

So, for the future they are now going to plan the NICHE-3 study maybe with a different immunotherapy compound and we are looking forward to these results. And we are looking forward to the further information we're going to get on this study, on the three-year disease-free survival, which we will await in 2023.