Educational content on VJOncology is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.

Welcome to the GI Cancer Sessions with the Video Journal of Oncology (VJOncology.com).

Following an exciting day at the ESMO 2022 meeting in Paris, France, leading gastrointestinal cancer experts get together to share their highlights. Join Geoffrey Ku and Sam Klempner as they dissect key updates in upper GI cancer.

 

Welcome to the GI Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).

Following an exciting day at the ESMO 2022 meeting in Paris, France, leading gastrointestinal cancer experts get together to share their highlights. Join Geoffrey Ku and Sam Klempner as they dissect key updates in upper GI cancer. Topics covered include updates from DESTINYGastric-02 (NCT04014075) and MOONLIGHT (NCT03647969), as well as discussions on the optimal use of immunotherapy for patients with upper GI cancers. We also hear about research into potential novel biomarkers that could help with overcoming the immunosuppressive tumor microenvironment.

Transcript

Geoffrey Ku:

So, welcome to the upper GI session at ESMO 2022. My name is Geoffrey Ku. I’m a GI medical oncologist in Memorial Sloan Kettering. I’m pleased to be standing next to my friend and colleague.

Sam Klempner:

Hey, I’m Sam Klempner. I’m a GI medical oncologist at Mass General in Boston, Massachusetts.

Geoffrey Ku:

And so, the topic today really is what advances or what are the latest updates in upper GI cancers here at ESMO? So, maybe I’ll start off with a mini oral presentation that I gave focusing on updated data from DESTINY-Gastric02, which is a second-line study of trastuzumab deruxtecan or T-DXd in patients with HER2-positive esophagogastric cancer, who previously received their trastuzumab containing regimen. This was a purely western population enrolling in North America, as well as Western Europe. The initial data actually were presented at ESMO last year, and in this update, we essentially confirmed the high activity of the regimen. The response rate is 41.8%. We are also able to estimate for the first time median overall survival of 12.1 months. Toxicities are otherwise as previously reported, and consistent with the known toxicities of T-DXd. In particular, it is important for clinicians to be aware of the risk of interstitial lung disease and pneumonitis, because unfortunately there were two patients on this study who had fatal events. Sam?

Sam Klempner:

Yeah, Geoff, I think it was great to see you presenting that data. It’s certainly important, and I think it does highlight the activity of this drug in the second-line space. And also, I thought it was an excellent point by the discussant that it would be wonderful to see this drug become available to our European colleagues. In the United States, we’re lucky enough to have access to T-DXd in second-line and beyond.

Geoffrey Ku:

Yeah, no, you’re absolutely right. And it is interesting that in the US T-DXd actually was approved, not on the basis of this study, but on the basis of DESTINY-Gastric01, which as you know, was an East Asian study that actually was a randomized study looking at T-DXd versus dealer’s choice of chemotherapy in the third-line setting. So, it’s interesting that the US accepted ex-US data in the third line setting and approved it as post-trastuzumab therapy, which means really it can be given a second-line therapy, which I think many of us are doing. I’m sure you know also that there is a globally outside of the US, there is a Phase III study DESTINY-Gastric04, which is a randomization between T-DXd, and the standard of care, which is ramucirumab paclitaxel. I think there are many places in the world that await or require the results of a randomized study in order for regulatory approval in the second-line setting.

Sam Klempner:

Yeah, I agree. I think that will be an important trial. It’s also a nice way for some of the participating sites to gain access to ramucirumab, which is also not approved in unfortunately many of these countries. Unfortunately, we did see some other maybe not as exciting evidence in the second-line space for gastroesophageal adenocarcinomas, which has been quite a difficult space to enter in drug development due to the poor prognosis of these patients. But we did see a recent presentation for a trial called the DURAGAST, which was asking the question of whether or not combining PD-1 or PD-1 plus CTLA-4 on top of second-line chemotherapy with FOLFIRI would improve the progression-free survival rate at four months. And unfortunately, neither arm met the pre-specified signal, which was 70% progression-free survival at four months. And it’s just another dataset that unfortunately reminds us how difficult it is to move into this space, and these were actually all PD-L1, and PD-1 treated naive patients.

Geoffrey Ku:

All right. So, I think what’s also challenging about interpreting those results is that they use FOLFIRI as a backbone. I think we just mentioned that I think most people… Certainly, I think in North America and Asia, we would consider ramucirumab/paclitaxel to be the standard of care. Now, FOLFIRI is probably as active as paclitaxel, but I think without the ramucirumab component, it does make it a little bit challenging.

We talked a little bit about the results of DURAGAST before this. One thing that was interesting is that in the patients who receive FOLFIRI, durvalumab, and tremelimumab, the median overall survival was strikingly long at 13 months. But again, this is a small dataset and at this point we don’t have any biomarker data at all. All you need would be a couple of patients with MSI- or EBV-positive tumors, and that certainly could drive all of the benefit.

Sam Klempner:

Yeah. I think it’s all about biomarkers. And speaking of biomarkers, we can maybe talk a little bit about some of the first-line trials, and I’ll talk a little bit about a poster that we’re presenting, which is perhaps a biomarker that will become more relevant if the data continues to look promising. But, as we know, there’s a large proportion of patients who are PD-L1-positive or PD-L1-negative who may not be getting the significant degrees of benefit from the addition of PD-1 on top of chemo. So, one of the areas of interest is other biomarkers and Dkk1 expression may be an indicator of a more immunosuppressive microenvironment that is potentially targetable. So, there’s an IgG monoclonal antibody called DKN-01, which has previously shown activity in second-line and beyond patients in combination with pembrolizumab, and the notable activity was in the biomarker-enriched patients, the Dkk1-high patients.

And so based off of that, this was moved into the frontline in a cohort of a Phase I/II trial called DisTinGuish. And really, in the CAPOX plus tislelizumab, another PD-1 drug, plus DKN-01 arm, the response rate in the Dkk1-high patients was 90%. And this is certainly very encouraging in a small cohort and does go to support the ability to perhaps enrich for responding patients with this Dkk1 biomarker. And now, this will move to a randomized Phase II versus FOLFOX or CAPOX plus tislelizumab to see if these findings will hold in a larger 160 patient population.

Geoffrey Ku:

So, this is actually a great opportunity for you to educate me. So, Dkk is it some kind of immune checkpoint molecule and what’s the incidence in the high expressers?

Sam Klempner:

Yeah. So, Dkk1 is a protein that is expressed primarily on tumor cells and much less so in immune cells. High expression, at least in the screening patients coming on to the study, in the first-line was about 57%. So, if that prevalence holds true, then that would be very encouraging for a large biomarker-selected population. The effects of circulating Dkk1 and Dkk1-expression on tumors I think are incompletely elucidated. It is clearly has some immunosuppressive roles in that it promotes MDSC and Tregs, and may help exclude T cells from the microenvironment. And there may be some direct tumor-promoting effects when circulating DKK1 binds its receptor and via CCAP4 and directly stimulate tumor proliferation. So, it’s similar to some other modulatory agents that are probably multifactorial mechanisms.

Geoffrey Ku:

Okay. That’s fascinating. Any data about co-expression with, for example, PD-L1, HER2, any kind of clinical pathologic correlates? Is it more common in diffuse or intestinal, anything like that?

Sam Klempner:

It’s a really good point. So, the frontline population was all adenocarcinomas of GE junction and gastric. There is few diffuse patients. We don’t know about the diffuse first intestinal, but what we do know, and one of the immediate questions that came up during the frontline cohort was, “Are you just marking patients who were going to respond to checkpoint inhibitors anyway.” And so, it’s pretty clear that Dkk1 and PD-L1 expression do not have a relationship, and there was the distribution you would expect from a frontline population. It did not appear to enrich for any subset. And among the responders, when we tried to make statistical comparisons in the small cohort, there was no relationship between the two biomarkers. So, it seems that these are independent. We don’t have data for HER2. There was only one… No MSI patients that were known to be MSI in the trial so, it may be not very common in MSI high, but we don’t really know that from large series, yet.

Geoffrey Ku:

Okay. Oh, that’s really interesting. In the last couple of years, I’ve seen the dataset development become more enriched. I think the randomized Phase II study will be really exciting, and certainly here is hopeful…Here’s hoping that you recapitulate some of the data that you’re seeing in the single-arm studies, and potentially this can become a validated biomarker. Others may know that other biomarkers that are being looked at in the first-line setting our Claudin 18.2, FGFR2. No real data presented on any of those at this conference, but certainly it’d be great if we have more biomarker-selected populations.

Sam Klempner:

Yeah, I think we’re all eagerly awaiting those Phase III trials. Hopefully in the somewhat near future. What did you think of this other frontline dataset of this German Moonlight investigator-sponsored trial asking the question about adding dual checkpoint on top of frontline FOLFOX versus sequencing?

Geoffrey Ku:

Yeah. No, it’s interesting. Actually, when we talked about DURAGAST, which essentially is looking… is asking a question of combination PD-1, PD-L1 and CTLA-4 plus chemotherapy. Moonlight is also looking at that. My understanding is that it’s a multi-arm design, and they’re only just presenting two arms. But the two arms were so concurrent to FOLFOX with ipilumumab and nivolumab. In other words, building on the CheckMate-649 data by adding a CTLA-4 antibody, or something that people have talked about before with a sequential design, and the theoretical reasons why that may be a good idea. But FOLFOX followed by IPI/NIVO. Again, these are small datasets, and it’s hard to generalize too much, but it certainly seemed like the sequential design, so FOLFOX followed by IPI/NIVO, was not good. The response rate in PFS certainly worse than FOLFOX, significantly worse than nivolumab FOLFOX.

Sam Klempner:

Yeah, I agree. And I think we’ve seen attempts at switch maintenance or maintenance type strategies not quite pan out the way we were hoping. Getting back to the common theme of biomarkers, I think we all thought when the avelumab data came out that perhaps if they had only selected for PD-L1-positive patients at maybe a certain cutoff, they might have seen a positive result. And perhaps there are some patients that could benefit from a strategy like that. But it’ll be interesting to see tomorrow when the full data is presented if Dr. Lorenzen has any thoughts about selection strategies for future maintenance strategies.

Geoffrey Ku:

Yeah, and I think even the combination, even the IPI/NIVO arm with FOLFOX, again, these are small datasets and I think we have to be cautious, but on the surface of it doesn’t seem to be a strong signal. The response rate and even the PFS certainly seem in line with nivolumab FOLFOX.

Sam Klempner:

Yeah, I think themes of the conference continue to be biomarker development and really best patient, best drug, really patient selection for our trials to really improve the outcomes.

Geoffrey Ku:

All right. And maybe the last question I’ll leave is a rhetorical one is, are the days of CTLA-4 and PD1, PD-L1, is that doublet played out? It certainly never had led to a regulatory approval in esophagogastric, but certainly I think given the toxicities of CTLA-4 therapy, and other targets on the horizon LAG3, TIGIT, I think maybe we may be moving beyond that doublet.

Sam Klempner:

Yeah, I agree with you. Except I was curious about the subset of the MSI patients from 649 where they had some IPI/NIVO versus FOLFOX/NIVO data presented, and the IPI/NIVO data is interesting to look at, but hard to say that you would take a frontline MSI patient and do something other than PD1 versus chemo plus PD1.

Geoffrey Ku:

Right, right. So, yeah, I think it’s safe to say that. I think the theme of many of these conferences is biomarker development. I think it really remains imperative that we better understand the patients who are benefiting from our treatment, certainly, immunotherapy, but even cytotoxic chemotherapy, even to this day and we don’t have good biomarkers, I think the second-line space remains extremely challenging in terms of drug development for esophagogastric. I do think that T-DXd will eventually have a clear role in the second-line space based on Phase III data. But again, in the US at this point, the drug is approved for post-trastuzumab progression therapy, meaning that it can be given in second- or third-line.

Sam Klempner:

Yeah, I’m with you, and I think that hopefully with better drugs, we can revisit some of the targets where the results have perhaps not been as encouraging, and we just get better at understanding the biology and picking the patients. I know we’re both involved in some EGFR, and we’ve talked and thought about revisiting MET. Can we really select the patients who that strategy may be viable? These are good questions for the future, and hopefully future discussions together at another ESMO conference.

Geoffrey Ku:

Yeah. No. I think that’s a great question. I think pairing a better drug with a biomarker, it’s probably a more fruitful strategy than pairing a mediocre drug with a biomarker.

Disclosures

Recording date: 10-September-2022; Feature publication date: 11-October-2022.

Geoffrey Ku

Dr Ku reports the following disclosures:

Advisory/Consultancy: AstraZeneca, BMS, IMAB, Merck, Pieris, Zymeworks

Research Grant/Funding (Institution): AstraZeneca, BMS, CARSgen, IMAB, Merck, Pieris, Zymeworks

 

Sam Klempner

Dr Klempner reports the following disclosures:

Advisory Role: Astellas, Merck, BMS, Novartis, Daiichi-Sankyo, AstraZeneca, Sanofi-Aventis, Exact Sciences, Mersana, Coherus, Eli Lilly

Funding (institutional): Leap Therapeutics, Astellas, Arcus

Stock/Equity: Turning Point Therapeutics, Nuvalent