SECTION 1 – TOPAZ-1 in biliary tract cancer

NATALIYA UBOHA:
Hi, everybody, and thank you for joining the session on ASCO GI updates for VJOncology. My name is Nataliya Uboha and I’m an Associate Professor, Medical Oncology in University of Wisconsin. And I am delighted to have the true experts in the field with me today. Dr. Kristen Ciombor, who is an Associate Professor from Vanderbilt University, and Dr. Ghassan Abou-Alfa, who is a Professor at Memorial Sloan Kettering. Thank you so much for joining me, and I am excited to have a very fruitful discussion about the recent updates about GI cancers from GI ASCO. I was going to start with talking about pancreatic biliary cancers and Ghassan, if you could take us through some of the key studies. I was going to start with the TOPAZ study, which is a first line Phase III trial of durvalumab in combination with chemotherapy for advanced biliary tract cancers. Thank you.

GHASSAN ABOU-ALFA:
Well, thanks so much Nataliya, and thank you for having us, it’s a great delight. And I have to start by saying, first thing, is that congratulations to ASCO. This was a beyond successful meeting, and you hit it right on to have the hepato-pancreato-billary first because whoa, like you know, this was like, we didn’t even mention it in the meeting and this was really like the mover and shaker of this GI ASCO this year.

So you hit it right on, TOPAZ, a quite impressive effort. And this is led by our dear colleague Dr Oh from South Korea. And it is really a very straightforward concept. How can we add on a checkpoint inhibitor to chemotherapy? And this is of course based on many of the theories that we had before with regard to probably a certain priming and a certain kind of you know, continuation with the checkpoint inhibitor afterwards. So you can consider it bold, but impressive where the patients were randomized to either gemcitabine and cisplatin, which is a standard of care therapy, up to eight cycles. Same way our colleagues in England did try the ABC-02 with Dr Valle and colleagues. And these patients were, either had on GemCis plus durvalumab as an anti-PD-L1 versus GemCis and a placebo. So clearly it was randomization for standard of care therapy for up to eight cycles plus or minus durvalumab.

And the data of patients that you know, were about like close to about 700 in the study, came out positive with an improvement to survival, a 12.8 month median survival for the durvalumab plus GemCis versus 11.5 month for the GemCis plus placebo. Now here, you can read things a little bit in different ways and people might say oh, wait a minute. This is not much. Well it is, because statistically it was significant and clinically significant, as you can see from the responses that we have on. More importantly, we have to start all of us train our mind and kind of you know, its thinking process, how we look at survivals when it comes to checkpoint inhibitors. And if anything, the curves really continued to spread out over time, enough that really we had by 24 months, a clear continued improvement. 24% of the patients, one quarter of the patients were still alive at 24 months or two years versus 10% for the GemCis. And the cutoff was kind of like for spreading of the curves, started around nine months. Really this is where the separation is. Because yes, of course it takes time to prime the immune response to get this benefit from therapy. So I think all in all, it was a great study. And by all means, I would say many of us already are practicing and adding durvalumab to the patients in first line for biliary cancers after GemCis.

NATALIYA UBOHA:
So Ghassan, I wanted to ask your opinion about the design of the study. They stopped chemotherapy after six months. Is that what you do in your practice, and Kristen please comment as well. What do you do after six months of GemCis, which is, I agree the way ABC-02 was designed.

GHASSAN ABOU-ALFA:
I would say that as you and I know in the US, we just continue therapy until intolerance or until progression, but no doubt that the add on of durvalumab, is giving us a different perspective now, i.e. is it that the priming with the GemCis and durvalumab and continuation of the durvalumab as maintenance therapy a novel perspective? By all means, why not? I mean, the data is in front of us and the patients would love that because after all, the side effects from the gemcitabine and cisplatin are not necessarily like the ones that people would aspire for. And at the same time, we know very well, if people try durvalumab, especially within the eight weeks where really the continuation of the whole potential spectrum of side effects is all gone, I would say that, why not? I will say we’re comfortable continuing only with durvalumab after eight cycles of chemotherapy.

KRISTEN CIOMBOR:
That’s great to hear you say that Ghassan, ‘Cause I was sort of leaning that way as well. You know, when I give GemCis, I do tend to continue it as long as it’s tolerated, but this gives us an opportunity to stop, I think, without stopping therapy completely. So I think that’s very, a very welcome result.

NATALIYA UBOHA:
Yeah, no, I was excited to see a positive study. I agree. We were way overdue for a positive study in this space. I am excited about GemCis abraxane Phase III study that’s run by Dr Rachna Shroff. Although I do appreciate that the triple chemotherapy is not going to be an option for all of our patients because of performance status. I think it’ll be interesting to see some of the subgroup analysis going forward with molecular testing and MSI testing, which were not presented at this meeting, but hopefully we will glean who are the patients to benefit. And then last question that I had also about the subgroup analysis that you probably have noticed they look by Asian versus non-Asian patients and Asian versus non-Asian countries and it really was no benefit in non-Asian countries. So I’m curious as to how we should interpret it in the US in terms of incorporating this.

GHASSAN ABOU-ALFA:
Sure, no by all means. Thanks very much Nataliya. If anything, everybody asks the same question and everybody keep continue to ask the same question, and if anything, we have to however, put a subgroup analysis within its limited context. It’s a subgroup analysis. And if anything, the benefit, I would say was noted among all different variables among which the Asian/non-Asian is still despite that the hazard ratio for the non-Asian was closer to the cutoff of one, but still it was within the realm of the durvalumab GemCis.

Now, could it be that there are other variables here to play a role? By all means. Actually when we come to talk and I think you’re gonna ask me about HIMALAYA as well, the patients in Asia appear to be, for what we presume, either it is because of a potential infection in the hepatocellular carcinoma, for example, or even the ethnicity itself can really make it a little bit more prone to benefit from the checkpoint inhibitors. This is all theory. I really cannot in any way claim that if I have patient who is non-Asian tell them, no no, I would not give you durvalumab. We are giving it to everybody. At this point in time, the subgroup analysis within this context, yes, is showing some subtle variation, but nothing crossed the hazard ratio cut off of one to decide no, there’s no benefit there. There’s still benefit. It’s a matter of just maybe delineating further of this and better understanding it. But at this moment it’s available for everybody. It should be available for everybody.

NATALIYA UBOHA:
Thank you so much. This was great, great discussion.

SECTION 2 – HIMALAYA & KRYSTAL-1

NATALIYA UBOHA:
We are going to move towards HCC now. Durvalumab and tremelimumab in HCC, the HIMALAYA trial, and you did a great discussion already of this at ASCO in the in person meeting. But if you could walk us through the study and the results, that would be great. Thank you.

GHASSAN ABOU-ALFA:
No, thanks so much Nataliya again, and a full disclosure, as you all know, I, on behalf of all dear colleagues, I’m the one who presented the HIMALAYA. That was a great, great honor. And if anything, at ASCO I kind of like started by the results and everybody asked me why. ‘Cause you know what, everybody was waiting for this. And you know, because it’s so robust, positive study, by all means you know, let’s just see it because more importantly, and I give you credit Nataliya, exactly, let’s learn what exactly is going on. The concept of it is beyond fascinating, because the idea is that at the cell membrane level, we have the T-cells trying to come attack the cancer. We already tried that with regard to the anti-PD-1, anti-PD-L1 as single agent. And we know very well they did not really imply that much of a valuable added response. However, when we start getting some priming from whatever it is, being VEGF, FGF, and there have been a lot of trials, some of them are greatly positive for that purpose, then definitely you will get more benefit.

Interestingly, now we’re going all the way to the top of the chain of command, because CTLA-4 lodged in the lymph node, and interestingly, CTLA-4 can really hijack away CD80/86, which send the message all the way to the anti-PD-1, anti- PD-L1, and anti-CTLA-4 comes to take away that kind of you know, blocking the CD80/86 from causing the effect and gets it to be more efficient. Interestingly which we, I personally didn’t know that, but what’s fascinating, anti-CTLA-4 has three times more potency than even the normal molecule of CD28 that enhanced CD80/86. As such, came out with the idea, and this is where the novelty is, one dose. One dose only of tremelimumab is enough to induce that effect.

So the study as such was randomizing patients for the durvalumab plus tremelimumab with tremelimumab given only one dose at 300 milligram, versus durvalumab, a single agent anti-PD-L1. Understandably, remember the study started at a time when still these things are being looked into. And thirdly, of course we had the reference, which is the sorafenib. The study’s primary endpoint was to compare the durvalumab plus tremelimumab to sorafenib looking for superiority for overall survival, but also it looked at durvalumab versus sorafenib looking for non-inferiority based on prior data done with other trials that we all were involved in. This study, if anything came positive and it showed that there is clearly an improvement in survival for the tremelimumab plus durvalumab, with a median of 16.4 months for the T300 plus D and of 13.8 month for sorafenib. Clinically and statistically significant. If anything, it also showed the non-inferiority that we were looking for, durvalumab versus sorafenib 16.6 and 13.8, and if anything, the hazard ratio was 0.86 for that one, totally noninferiority matching between durvalumab and sorafenib.

So I think it really kind of like it’s like one stone hit two birds. If anything, number one, we have clearly a new novel approach of one dose of tremelimumab plus durvalumab as a improvement of survival compared to standard of care sorafenib. And of course number two is, and I’m not sure who are those patients who gonna get durvalumab only, but of course durvalumab is as good as sorafenib, was of course, a way better toxicity as we already presented as well, where the grade three and four toxicity was mainly with the sorafenib.

NATALIYA UBOHA:
Thank you. This was great. And an obvious question is how does this compare to IMbrave? We should never do cross trial comparisons, but we always do them. And numerically the overall survival in IMbrave was a bit longer, so, thoughts?

GHASSAN ABOU-ALFA:
Well, you are right. We should not do them. And that’s why we should not talk about, I’m just kidding. So I can tell you, my way from the hotel to GI ASCO, and before I present the HIMALAYA study, I was asked about the IMbrave150 comparison 12 times on the street. So I can understand why we’re doing this, to be fair.

Number one, they are both great products. I mean, no question about it, these are both robust clinical trials, positive data, no question about it. Number two, the comparison is unfair because we’re really comparing apples and oranges. Because if anything, the add on of the bevacizumab its the anti-VEGF level activity that happened very close to where the anti-PD-1 anti-PD-L1 activity happens at the cell membrane. While anti-CTLA-4 is something which is happening at a very different place, which is all the way in the lymph node. So to be fair, we’re now, if anything, not comparing the study, we’re comparing outcomes.

Now, when it comes to outcome, this where we have to start dissecting and analyzing different ways. Number one is, the patient population was not necessarily equal. To be fair, these studies were done in different setups. And if anything, there’s a certain robustness of the patients in Asia. We just spoke about it for the TOPAZ. In regard to the IMbrave150, we had a much broader perspective of patients from literally all over the world, all over the world, in regard to the HIMALAYA, which give us a little bit of a more, a broader perspective about how everybody did benefit, regardless of where they’re coming from or where the technology is. Number two is, with the IMbrave150, again, as we’ve been anticipating the patients with the hepatitis B might fare better. And frankly we see it ourselves also. So it’s not like anything.

So now if you weigh things in, yes, of course you might see a little bit of difference than [inaudible] IMbrave150, but again, I would say it’s maybe an unfair comparator over here. And number two is, we come now to the other things. Usually, you know me, I had to refrain from those questions because respectfully I, yes, do acknowledge and do appreciate that we have two great products in front of us, but by all means the anti-drug antibody issue is a serious issue in regard to the IMbrave150. 30% of the patients have actually anti-drug antibody, which means their hazard ratio goes all the way down, close to one, i.e. Bev plus Atezo is as equal as to sorafenib, and interestingly, we cannot tell in advance who are those patients. We cannot tell even after this happens, who are or who were those patients. We cannot even test for this. So we’re taking already a 30% chance, one third chance. We’re gonna tell patients you know what, I can give you all that Atezo and all of that Bev and all that kind of you know, work up for it, and guess what it might be equal to sorafenib in 30% of the time. So that’s an important thing. And remember, even the FDA was very clear about it and put it even in the package insert for that purpose.

Number two is the issue of the endoscopies. This is not really a no sweat issue. Number one, and please, please, I urge everybody by you all means, if you decide to go atezo/bev, which is a great, again, combination therapy, but please make sure you scope patients. Sadly, it’s kind of becoming a little bit relaxed, they say, “I don’t think they have a worry about varices.” Varices can happen. And as we know, when a varix opens, it really opens up and people can bleed to death. And did this happen on the bevacizumab single agent therapies before. So if anything doing the endoscopies, this can definitely cause a certain delay, but we have to do it for the atezo/bev. Number two is when we do the endoscopy, we have to make sure we read it right, because remember one thing, the best endoscopists for varices are the hepatologist. They’re not gastroenterologists. Because hepatologists work in transplant, you know, in the transplant field, this really where the most varices are being evaluated. And you don’t want, sometimes, a certain varix to be over appreciated where otherwise we deny atezo/bev for our patient because we thought this is really serious. But at the same time, we also don’t want a certain varix to be underappreciated where we say, “Ah, it’s not an issue and our patient is bleeding.” So I think there’s a lot of, kind of, you know, if and buts about this that we really have to think about. Again, I’m not necessarily vouching for one versus the other, but I’m trying to really delineate differences. And of course it’s all up to our judgment what we think is best for our patients.

NATALIYA UBOHA:
I agree. I think it’s great to have options for our patients. And I thought this was a great study. I was impressed with just one dose of anti-CTLA-4 antibody. Kristin, what do you think about maybe incorporating just one dose of anti-CTLA-4 in MSI-high colorectal cancer patients? I think we use, in the prior studies, these types of agents we use on an ongoing basis.

KRISTEN CIOMBOR:
Yeah, exactly. And there are a lot of parallels that we wonder how come, how we can compare between the tumor types. So you know, I think that’s a big question in an MSI high colon cancer, just, whether we need the CTLA-4 antibody at all, and how we use that most effectively. Most of the studies unfortunately have used the lower dose of IPI, in particular. But it definitely is an ongoing question that we need to answer.

NATALIYA UBOHA:
And moving on to the other study, which I thought was a splash, a small study, but that data was adagrasib which already was presented in colorectal cancer at ESMO, now presented in pancreas and other GI cancers, I thought was quite impressive. Curious to hear your thoughts and also how do we actually get this drug based on this small dataset to patients in clinic if we were to find one patient with that rare mutation.

GHASSAN ABOU-ALFA:
Yeah, thanks very much Nataliya. I’m so happy you bring up the KRYSTAL. If anything, I give credit to the whole team. And I think Dr. Bekaii-Saab, an incredible doctor, he, as always, did an amazing job in presenting it, despite this is a very limited number of patients. And if anything, he beautifully presented to us that patients with KRAS G12C if anything, and this is a population that doesn’t apply to many cancers, but the aim was to show it in the GI because we were in GI ASCO as he currently mentioned that as well. Impressively, despite the limited number of patients and mainly they were the ones you like to focus on, and I totally agree, were the pancreatic and the biliary cancers, despite the limited number of patients, 100% response, whoa. There were really a lot of partial responses and a lot of stability of disease, which if anything, really gives us an opportunity to show that the median of the response was about like seven and a half months, as he mentioned, on the average for the two.

Interestingly, he brought up lot of questions and these are very valid questions, very thought of. Number one is, what should we do with this? This is definitely kind of like now we have, remember, already reported data on the sotorasib, and this already, as we all know, was published in New England. I give a lot of credit and this is like really my dear colleague who does lung, Bob Lee at Sloan Kettering and we kind of like learn from each other. And I was like beyond fascinated how we’re gonna be ultimately trying to understand those two drugs per se. But I think despite the limited number of patients in the study, this is a positive study. And I totally agree with you. This definitely could be practice changing, no question about it.

The question that I really bring up, however, not only for that specific study, but also for the whole concept together. Remember back in the sixties, when we’re doing a clinical trial, you know, you bring in another certain number of patients statistically, you calculate a number, you compare this kind of bunch of patients to patients that received placebo or standard of care. You see if they did better or not and then decide on standard of care. On the average, studies might be at 300 patients. They can jump onto 600 patients, and look at this HIMALAYA was 1300 patients. And the question is when we come now to pancreatic cancer or even to go even further than that, biliary cancer, which is a rare cancer to begin with relatively speaking all over the world, even though there are certain [inaudible] where there’s more patients with biliary cancers, and now with a mutation that will represent at best 1% of the patients, how we can try to get this to where it is? So this is where I really, I give, serious, a lot of credit and accolade for how the FDA did approve the sotorasib. And if anything, we have to really bring in a certain novel approach of understanding that these populations are not to be randomized and compared to not giving the drug. Number one is what is the ethical perspective of knowing that a mutation can benefit from a certain therapy? We know very well the response is high, and what’s the idea like to look at survivals? I think survival is key. We still stick by it. We saw already to example, TOPAZ and HIMALAYA where survival is critical, more than even PFS. PFS, who cares. But interestingly, however, in other settings response, like as we just saw, as well as progression-free survival might be valuable. So I think this is gonna again, remind us again of the importance of now we have to go to version 2.0, how drugs are ready to get available and become available for patients, not only depend on large trials and randomization against the placebo or standard of care.

NATALIYA UBOHA:
No, absolutely. Seeing those kinds of waterfall pots for patients with pancreas and other pancreaticobiliary cancer is impressive. Good news is we already have some experience with larotrectinib and NTRK inhibitors, which were approved based on Phase II data. So hopefully we’ll be able to get these drugs to clinic soon. But I would like to thank you so much for this excellent discussion of this.

SECTION 3 – CIRCULATE-Japan & incorporating ctDNA in the clinic

NATALIYA UBOHA:
I would like to shift gears and talk a little bit about colorectal cancers now. And Kristen, if you could give us some updates on the, there was a lot of talk about circulating tumor DNA and colorectal cancer. How do we start, and in other GI cancer. So we, you know, certainly will be curious to hear what, how Ghassan is using these tests as well, but can you tell us a little bit about the CIRCULATE Japan and what new information have you learned from that study compared to what we known thus far?

KRISTEN CIOMBOR:
Yeah, so we were all eagerly anticipating the CIRCULATE Japan data after knowing, you know, how that group has really led the way in terms of designing these studies, and CIRCULATE Japan was really that, or the, the portion that was presented at ASCO GI was really the observational cohort. What’s called the GALAXY study. There are ongoing randomized trials called VEGA and ALTAIR that we still are waiting, awaiting results from.

But really what was interesting is that there were many, many patients here represented and really along all stages of disease. So from stage one through stage four, and then they looked at different subsets, but what they really confirmed was the clearly prognostic value of circulating tumor DNA, particularly in the patients who undergo resection for colorectal cancer. So that was really nice data to see. We have seen that in smaller studies in the last few years, what we don’t have quite yet though, is really what we, we’re not exactly sure what to do with the information, and we’ll get there. We have ongoing studies that are looking at this very question, both in Japan, the US, all around the world, looking at these questions, but we clearly know that this is a prognostic tool and we just have to get more data to understand how to use this in clinical practice.

You know, what they showed was that the circulating tumor DNA positivity at four weeks postoperative was incredibly prognostic for ultimate outcome. And the curves were just beautifully separated. They also saw that with the addition of adjuvant chemotherapy, you saw clear differences in almost all subgroups, except for the patients who had negative ctDNA in the stage two disease. So again, very prognostic, not quite sure what to do with that information yet on a clinical basis personally, I am still enrolling patients in studies as much as possible, rather than using kind of off trial ctDNA testing. But I’m curious as to what you all do in your practice as well.

NATALIYA UBOHA:
I’ve incorporated ctDNA into the care of my patients. I don’t see as many colorectal cancer patients, but I started to also collect the information in my upper GI cancers in adjuvant setting and oligometastatic disease. I have to admit at this point, for me, it’s more of a, you know, learning exercise as to how to incorporate this test in my practice, but I have used it to pick up early recurrences. So more for surveillance purposes rather than to make treatment decisions based on the positivity or negativity. What about you Ghassan? Do you use this in for your patients?

GHASSAN ABOU-ALFA:
Yeah, no, I totally agree. If anything Kristen, you’re also right. And Nataliya just, you seconded it, which I think we’re all in the same place. We really don’t know yet what exactly it will mean. Interestingly, the first question we asked is totally legit, which is how does this correlate with what is exactly happening in the tissue of the tumor? And we tried to do like, you know, or at least we thought of like, biopsies and repeat biopsies and compare ctDNA. Actually, I don’t think really it’s gonna be the right exercise. And that’s what nicely Kristen just presented to us is how can we correlate ctDNA with outcome? That’s really where the exercise is gonna be.

So at the moment, do we practice it? Yes and no. It depends if really it’s part of a trial. And number two is if really there is any, at least suggestion, not necessarily full evidence, but suggestion, that it can be beneficial, but at the same time we might refrain from it as a quick look way as patients would love to, that yes, you have a cancer or not because to be fair, we don’t have this full evidence yet for every disease. So I would say we’re still all in the same bag. Yes, it’s available to us. Yes, it’s a very powerful research tool, but at the same time, it’s accessibility for a common use, agnostically, it’s not there yet.

NATALIYA UBOHA:
I was impressed to see that adjuvant chemotherapy cleared like positive circulating tumor DNA in 68% of patients. I mean, this is what we hoped chemotherapy would do, but I thought this is the first time it was actually presented. Am I correct on this Kristen?

KRISTEN CIOMBOR:
Yeah, certainly in this sample size, you know, to see those clear trends was really nice because the longitudinal testing, I think is what’s really key here. And that was nice to really see confirmation that adjuvant chemotherapy in many instances in these patients with the postop positive ctDNA, you know, can be very prognostic.

NATALIYA UBOHA:
That was reassuring that what we are doing at least works and hopefully we’ll be able to actually use these tests to actually guide therapy.

SECTION 4 – ACCENT/IDEA & PD-1 blockade in MSI-high rectal cancer

NATALIYA UBOHA:
Speaking of guiding therapy in adjuvant setting, I thought the results from the ACCENT IDEA, large study over 11,000 patients was also interesting and potentially practice changing, or at least reassuring to us about our ability to deescalate therapy as needed. Can you walk us through this one please?

KRISTEN CIOMBOR:
Yeah, so I do think that this is practice changing or at least practice confirming. I think many of us kind of do this in practice and I’ll explain what they showed, but it was really nice confirmatory data, that probably our idea about how important oxaliplatin is and that in the adjuvant colorectal spaces is really key. So what they looked at, they did look at the idea in the ACCENT database. So this as you said, over 11,000 patients. Patients, they looked at early treatment discontinuation. So this was only patients who were intended to receive six months of adjuvant chemotherapy, whether that be CAPOX or FOLFOX. And then they looked at the, essentially the relative dose intensity that was received by patients. And they also looked at the early oxaliplatin discontinuation.

And the ultimate takeaways were that it was not, it did affect survival if you stopped treatment early, earlier than six months. However, stopping oxaliplatin, as long as the patients had received at least 50% of the planned six months, really didn’t affect survival. And that was what was really a nice takeaway because ultimately in clinic, that’s what we do anyway. You know, we are very worried about leaving, curing someone from their cancer and leaving them with irreversible neuropathy. And so I think all of us between that three to six month mark, we have a very low threshold for dose reduction of oxaliplatin or even stopping it altogether. And even with our best experience, we still leave patients with neuropathy sometimes.

So, I think it was really nice to see. In fact, I had this conversation last week with a patient. It was very relevant to my practice, and how we felt so much more comfortable dropping the oxaliplatin after that three months instead of really pushing forward to the six months. So that was really nice. I thought it was a very practical study. It’ll be really nice to see more information come out from that study as well. And we’re learning so much through that one, that one overall collaborative effort. And I think we will continue to as well.

NATALIYA UBOHA:
Yeah, thanks so much Kristen. Great summary. And I agree. I thought we struggled between stopping chemo after three months in some patients, especially patients that are young, but this was a very, the study that reassures a lot of our practices. It’s hard to give oxaliplatin for six months. It’s nice to know that we can deescalate after three months and we’re not compromising patient outcomes. I thought this was a great data set.

KRISTEN CIOMBOR:
And I think it’s becoming even more relevant because the incidence of colorectal cancer is I mean, younger and younger patients. So I have patients in their twenties and thirties who it really matters if you leave them with irreversible toxicity, but cure their cancer. So you really don’t wanna take any chances and compromise their cure, but you need to be careful with toxicity too. So I think it’s just gonna become increasingly important.

NATALIYA UBOHA:
Excellent. I would really like for you to comment on the data of by Dr. Lumish about MSI-high rectal cancer. And I know that you’re also leading the national efforts to get the largest study open for this patient population. I thought that data was very impressive. Similar data was presented with perioperative immunotherapy in gastric MSI-high gastric cancer as well. So we are really carving out this subset of these diseases where chemo may not even play a role.

KRISTEN CIOMBOR:
Yeah, I thought the Memorial data presented at as ASCO GI by Melissa Lumish was really provocative, and really nice to see. So what they, what she presented was this was a Phase II single institution study. It’s ongoing. In patients with MSI-high, locally advanced rectal cancer, they received dostarlimab. So PD-1 blockade alone, and then basically received that for nine cycles and then underwent reassessment. And that included endoscopic reassessment as well as radiographic.

And what they found was that you know, this is early, it was only 11 patients evaluable thus far, but the clinical complete response rate was a 100%. And those patients thus far have not required radiation or surgery or the other treatment modalities that we typically think are required for rectal cancer. So this was really nice to see. It sort of parallels the early stage colon data that we saw from Myriam Chalabi in Nature a year or two ago as well, where even with a short course of in that case, NIVO-IPI, it really led to incredible responses pathologically in the MSI-high population. Now this is a small subset, but I would argue, you know, in a prevalent disease and again with younger and younger patients and more and Lynch syndrome and everything else, that it is definitely a relevant target.

As you mentioned, we’re leading the ECOG study 2201, it’s currently enrolling. What that study is looking at, a very similar population, locally advanced rectal cancer MSI-high, and patients are receiving NIVO-IPI and short course radiation. So again, no chemotherapy, and we’re looking at pathologic complete response as the primary endpoint there. So we really do hope over time and to, you know, leave behind, potentially, some of our standard therapies, and really helping patients to live longer and better. So, but I do think it is a little early, I don’t think this is practice changing at the current time. We need more data, but it’s a really nice first step to see.

NATALIYA UBOHA:
I agree. I thought this was a great study and really gives great, I guess rationale for the study that you designed and are leading nationally, and hopefully will get that data collected soon and available to us.

GHASSAN ABOU-ALFA:
Oh of course, we’re very proud of Melissa’s work. And this was a really great one.

KRISTEN CIOMBOR:

They’ve done a wonderful job. And really also showing, you know, Dr Cercek showing that in MSI-high patients, chemotherapy neoadjuvantly is really, there’s a high rate of progressive disease. So you know, a lot of rationale for avoiding chemotherapy if we can help it, not just from a toxicity perspective, but efficacy standpoint.

KRISTEN CIOMBOR:
Absolutely. We all have some of these, I’m sorry. We all have some of these patients in our practice. I’m sorry, go ahead Ghassan.

GHASSAN ABOU-ALFA:
No, I was just gonna say, I think as Kristen said, yes a very small population, but at the same time, it bring another important perspective beside all the great things that Kristen mentioned, the patient age is definitely something that you know, Andrea and the team are really highly focusing on, which sadly is the reality that younger and younger patients are getting cancer. So I think the median age was like close to 50 or so. So that’s really, again, one important reminder for us about like the population that we’re dealing with. Yeah.

NATALIYA UBOHA:
And I’m hoping when we use more circulating tumor DNA MRD type assays, we’ll have another tool to make sure that we are on the right track because it’s always, it’s always challenging when we change the standard of care in patients that have curative diseases right. Early stage, we have to make sure that we’re doing the right thing.

KRISTEN CIOMBOR:
I think that’s an incredibly important point because what we see with immunotherapy is that radiographic response doesn’t always equate to what’s going on with the tumor. You know, you can still have residual disease on scans that you then remove. And actually it turns out it’s just fibrosis. So I think the circulating tumor DNA, the MRD assays will be increasingly important. So we’re incorporating that into the studies as well, but you know, early to know, but definitely a good step forward here.

NATALIYA UBOHA:
Well, I thought we had a great discussion. I thank you so much for participating in this. And I certainly have learned a lot. I was wondering whether anybody has any closing remarks, anything else we should touch on upon before we close the session.

GHASSAN ABOU-ALFA:
We can’t thank you enough Nataliya. You did amazing and so nice to really bring up all those important studies, and you’re right, actually, I learned a lot from Kristen today. And again, thank you so much for moderating and helping us with the presentations today.

KRISTEN CIOMBOR:
Yeah. Thank you so much. And it’s great to be with you all, and hopefully in person at some point here soon. And, but you know, my takeaway from ASCO GI this year was really across all tumor types we’re seeing advances, and it’s so nice to see. You know, there have been times in the past where only one positive study you know, we look forward to, and now we we’re really seeing advances across tumor types. And it really means a lot. I know to our patients, but also to us. You know, to be able to provide those new opportunities for them as well.

NATALIYA UBOHA:
Cannot agree more. Again, thank you so much for participating. Thank you, VJOncology for inviting us.

[END]

Recording date: 22-Oct-2021; Webinar broadcast date: 04-Nov-2021; Feature publication date: 05-Nov-2021.

Nataliya Uboha:

• Stock and Other Ownership Interests (received by an immediate family member): Natera & Exact Sciences
• Consulting or Advisory Role (within last 24 months): Ipsen, AstraZeneca, Taiho Pharmaceutical, Incyte, QED Therapeutics, Astellas Pharma, Pfizer & Helsinn Therapeutics
• Research Funding (to institution): EMD Serono, Taiho Pharmaceutical, Lilly & Ipsen

Ghassan Abou-Alfa

• Research Support: Arcus, Astra Zeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed & Yiviva
• Consulting Support: Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector & Yiviva

Kristen Ciombor

• Research Grants (to institution): Incyte, BMS, Merck, Array, Daiichi Sankyo, Nucana and Pfizer/Calithera
• Consulting Support: Natera, Foundation Medicine, Taiho, Merck, Pfizer, Lilly/Loxo, Replimune and Array.