Immunotherapy in Gastroesophageal Cancers — Yelena Y Janjigian, MD

DR JANJIGIAN: Hello. My name is Dr Yelena Janjigian, and it’s a pleasure to be back together with Dr Neil Love to talk about updates in immunotherapy in gastroesophageal cancers. I am a medical oncologist and specialist in this disease, and I also oversee the GI oncology service at Memorial Sloan Kettering. These are my disclosures.

So we’ll start with perioperative adenocarcinoma. Adenocarcinoma of esophageal and gastroesophageal junction is the most common histology that we encounter in the Western population. And as you know, in Stage IV disease for adenocarcinomas, we’ve been able to use immunotherapy now for the last 2 years in combination with chemotherapy. And now, these immune checkpoint inhibitors are slowly entering the arena in early-stage disease. We know from lung cancer and bladder cancer and melanoma that doing these treatments before surgery may improve the chances of survival because of education of the immune system and expansion of tumor-specific T-cells. We already also know that in the adjuvant setting after chemoradiation and adjuvant PD-1 therapy can improve disease free survival in esophageal cancers. So these current 2 studies I’m going to be talking about is answering the question in perioperative, so before surgery, with combination of chemotherapy, can immunotherapy improve outcomes?

So 585 is the first study that tried to answer that question. It’s a study that predominantly focused on patients in Asia and there were although some US and Europe patients enrolled, that was a small population. And this was the first study and looked at combination of predominantly 2 drugs, chemotherapy, 5-FU/platinum, so usually capecitabine/cisplatin in combination with pembrolizumab. It was a complicated study design although the study met its primary — it’s secondary interim analysis of complete response improvement. So pembrolizumab did improve the percent of patients with complete response at the time of surgery by about 12%, so chemo versus chemo/IO.

Unfortunately, as you saw published recently and presented also at ASCO GI, these curves summarize there was no improvement in disease-free survival. So what we’re looking at here is Kaplan-Meier estimates both for the main cohort and then the FLOT cohort. And there was no improvement in survival. Unfortunately, although the curves do separate initially, they did not separate meaningfully or significantly. So pembrolizumab is not standard in this practice and should not be used in perioperative setting. Although it looks like it was close, there was no clinically statistically significant improvement.

So what about MATTERHORN? So the MATTERHORN study came second. It was a more modern study. And sometimes, it’s better to go second because you can learn from the history. And so in this study, we used just FLOT. We didn’t have 2 different cohorts of 2 versus 3. And we used the global standard for perioperative setting which is 3-drug combination of 5-FU, platinum and a taxane, so docetaxel, oxaliplatin and 5-FU.

And what we were able to demonstrate was that irrespective of the area of where the patient was treated, so this was a global study. For the first time, 19% of patients were treated out of Asia with FLOT, unheard of. So being able to globalize the approach was an important step forward. And also, irrespective of where you look, the improvement in path CR rate which also was a secondary endpoint was the same and ranged anywhere from 10 to 13%. So once again, the interim analysis for this study was also positive and it met the statistical significance for improvement in path CR rate.

And what’s important to see is that in that patient population, we also had nodal downstaging and 0 status rate was increased. And the rest we have to wait for. So adenocarcinoma, we don’t have immunotherapy in the perioperative setting, 585 was negative, MATTERHORN seems to be on track to perhaps be positive using FLOT regimen. But still too soon to say. It may readout as negative. Neil, you had a question?

DR LOVE: Yeah, I was curious about the correlations with PD-1 levels. And sometimes when people look at PD-1, they go it’s either greater than 1 or not. But how often do you see what you would consider to be PD-1 high in this situation? And what do you see if you look just at those patients?

DR JANJIGIAN: Yeah, that’s a great question. So similar to other studies, both of these studies show the trend that PD-L1 less than 1 patients, and MATTERHORN used TAP score which is very similar to CPS and, of course, KEYNOTE-585 used CPS score, suggesting that less than 1 patient probably don’t have a great benefit. Hard to know because especially in the MATTERHORN study, that sample was very small. It was literally 50 patients. And then the very high expressors CPS 10, you probably see in about 15 to 20% of the patients. CPS 5, depending on what dataset you look at, can be as high as 50 to 60%. It comes down to tumor quality and the pathologist. I think if you probably polled just regular medical oncologists practicing in the real world, what I’m hearing is they’re seeing about 25% positivity with CPS 5 or greater. And I think that speaks to the methodology, but also tumor content and quality. I think we have to take it with a grain of salt and not take it for granted that in Phase III studies, we have great tumor content. That’s part of the reason why they were allowed to go on the study, because there was sufficient tissue to randomize and stratify them. And if you get your regular doc whose pathologists or his endoscopists may not be great at getting great quality of the sample, the PD-L1 testing is not that accurate.

DR JANJIGIAN: Let’s pivot to what’s next for this disease. Can we think about addition of new or different types of chemotherapies? Should we consider combination of different immunotherapies? So the ESCORT-NEO study was an interesting study I thought to summarize this because it for the first time looked head-to-head in randomized setting at different types of taxanes. So there’s a thread in the literature in breast cancer and in lung cancer that the type of chemotherapy backbone may matter. And if you use chemotherapy that you have to give a lot of steroids with such as your paclitaxel regimen, it may not be as optimal for partnership with immunotherapy as, for example, nab paclitaxel where it’s a nanoparticle formula, you don’t have to give as much steroids because the patient won’t have an allergic reaction or nausea and overall, it’s better tolerated. So I was very — I found this study very provocative because it for the first time was able to demonstrate that having a nab paclitaxel backbone may actually yield a higher path CR rate. That was the best part about this study. I think everything else, I would take it with a grain of salt.

I don’t know if we need another anti-PD-1 therapy in the US market. So camrelizumab is another PD-1 therapy that was developed with this study. But my take away from this was the path CR rate. With the nab paclitaxel, which was 28% compared to taxane, which was 15%, and certainly without any immunotherapy, it was 4.7%. This is a squamous cell population, so different than the adeno population that we talked about. But it’s provocative data. It makes me want to see more studies with nab paclitaxel backbone either in early-stage or even Stage IV disease.

Of course, if you recall, right now for adenocarcinoma in second-line setting, we don’t have good options for immunotherapy combinations. And paclitaxel is the standard in second-line setting in adenocarcinomas. So perhaps we should think differently. Nab paclitaxel is actually used in Japan. It’s part of their standard practice and available for gastric adenocarcinoma patients. It’s not part of NCCN guidelines or other guidelines in the United States for gastric cancer or esophageal cancer. Go ahead, Neil.

DR LOVE: It’s just so interesting. I’ve been hearing for years that supportive care with corticosteroids whether it’s for nausea and vomiting, et cetera, doesn’t affect efficacy of checkpoint inhibitors. But is there really data? And actually does it affect it?

DR JANJIGIAN: Well I think the best data that goes along with this is the CheckMate 649 data, right? And we know that if the patient has adverse events related to steroids for melanoma or other data that if you reverse the adverse events — I’m sorry, adverse events related from immunotherapy and you reverse them with steroids, the patient will still have as good a response or duration of response. But that’s, I think, a different question, right? Because if the patient is having immune-related adverse events, clearly, the immune system is active. The correlative of it is we don’t know that well. And I think similar with the use of antibiotics or probiotics or other sort of approaches, I think in general, less is more. If we can avoid steroids, I would. But the reality is to improve tolerance of chemo in most patients, we do need to use them still. But I thought it was very provocative data about the potential of activation of immune system in different ways maybe inducing more ADCC using the nanoparticle formula and perhaps less steroids. So we don’t know what the contribution of components would be.

DR LOVE: Maybe people would be more aggressive with nonsteroidal supportive care if they thought that.

DR JANJIGIAN: Yeah, right. I think we’re in uncharted territory here. But I think also it’s critical to continue to do symptom support so you can get the patients through as much treatment as you can, right? Because the patients, you know, what we need to remember is the Grade 3/4 toxicities associated from combination therapy by and large are from chemotherapy. And so these are important reminders for us.

DR LOVE: Interesting. Okay, please continue.

DR JANJIGIAN: Okay, great. So I think continuing along on perioperative or adjuvant perioperative therapy. I mentioned this 577 data. It’s a bit of an older data set already. It’s been published a while back. But this led to the FDA approval of nivolumab in the adjuvant setting after chemoradiation and surgery. Both in adeno and squamous cancers, if you have residual either T or node-positive disease, nivolumab is approved. So this is a nice abstract that looked actually at the PD-L1 expression after chemoradiation and before surgery or at the time of surgery. So the whole hypothesis that radiation can change the immune milieu and maybe the PD-L1 levels can go up. But I don’t know if it’s really the point here. I think mostly if you have residual tumor that has enough sample to get PD-L1 testing and if that sample is positive, it’s essentially like having Stage IV disease, right? We know that if you have residual disease after chemo/RT, your likelihood of recurrence is essentially very high within the first year. Most of these patients recur. So what I’m seeing this is really as confirmation of every other Stage IV study showing that immunotherapy works better in PD-L1 high patients. There’s more benefit. So that was a nice confirmation to see, not surprising. It just highlights the importance to continue to test for PD-L1. Test and retest on several samples to understand the change and the fluctuation in the disease biology.

So pivoting to Stage IV disease. We are seeing these updates, now long-term updates from Stage IV studies which is something new and nice to see to be able to do — we are about to publish the 3-year update from CheckMate 649 in JCO that’s about to come out. And this is a 4-year update from CheckMate 649 once again just showing sustained separation of the curve. So for these, as more and more targeted therapies are entering in the first-line setting, I think the shape of the curve will continue to be important to monitor. Because if at any point you see that the curves converge and overlap is when you start thinking, how do I prioritize therapies? And how do I plan ahead for the next steps for our patients. The fact that with immunotherapy, the curves, both survival and progression free survival curves, continue to separate and irrespective of PD-1 but also particularly for PD-L1 high patients, there’s survivors, long-term survivors. It is very important to see.

What we also need to start thinking about is prioritization of treatment based on their response rate and also improvement of quality-of-life. And what this data presented at ASCO GI by Dr Shitara shows that if you respond at 18 weeks, so we get these scans every 2 months or so. So if you’re responding at 18 weeks by partial response, the likelihood you’re going to be alive at 4 years is even better which is not sort of surprising to see. But as we’re seeing more and more agents being presented without response improvement, with just survival benefit such as claudin inhibitors, for example, zolbetuximab. Or if you wanted to talk about other diseases, we see that in melanoma with TIGIT inhibitors, right? But here, we’re clearly demonstrating it’s important to have a response because if you have a response, later on you’re more likely to benefit and continue to benefit durably.

So pivoting to now pembrolizumab. Of course, what we know about these PD-1 agents, essentially they’re very similar. We have a plethora of them approved in the United States, so both pembrolizumab and nivolumab approved. And so we can’t talk about CheckMate 649 data without talking about KEYNOTE-859 data. This was another study that was done later and readout a little later, but led to the FDA approval of pembrolizumab. It’s a multicenter, also HER2-negative cohort.

And once again, they’re presenting now long-term survivor results. And this is published as well. You see here because it was a later study, the median follow-up is a little shorter and the data that’s presented is a little less mature at 2 or 3-year follow-up now. But we’re seeing very similar benefit. Very similar shape of the curves. Again, PD-1 high population tends to do better. PD-1 low, the benefit is questionable. And now, we’re really urging everyone to test for MSI, PD-1, HER2 routinely and now claudin are coming.

So shifting gears to Stage IV squamous cell cancer. We keep going back and forth. But in the United States, squamous cancer is less common but it’s still worldwide the most common esophageal cancer, so it’s important to continue to keep updated on this. The 648 study looked at combination of chemotherapy with nivolumab compared to chemotherapy and also nivo/ipi combination, so chemo-free backbone was compared to chemotherapy.

And once again, they’ve presented long-term outcomes but also biomarker data. And what we’re seeing is that there are some inflammatory signatures by RNA-Seq and also TReg signatures by RNA-Seq. So when we talk about biomarker, we usually talk about immunohistochemistry or DNA-based biomarkers, mutations. Here, these are RNA-Seq data that’s bulk RNA-Seq done on paraffin tissue before the patients went on the study. So having high stroma is usually not a good thing to respond to immune checkpoint blockade. And having high inflammatory signature is good. So these were some of the biomarker data. It’s not practice changing. We should not drop everything and start getting RNA-Seq on everyone. But, again, as we’re developing future treatments and future enrichment strategies, this is helpful data. Go ahead, Neil.

DR LOVE: So we hear about RNA assays. When I hear about RNA assays, I think about fusions when people are looking for things. Is this one specific biomarker that you’re looking at or a panel? What is RNA-Seq?

DR JANJIGIAN: Yes, that’s a great question. So this is not like a lung cancer CLIA approved RNA assay that looks at fusion.

DR LOVE: Right.

DR JANJIGIAN: This is bulk RNA-Seq. So it’s a scientific method that is done and there are these 15, 20, 30-gene panels that are developed and validated in the lab. So it’s not CLIA approved. It’s a research test only. What’s interesting is that the TReg assay that is used in the study actually only has 2 genes. So in the future if we wanted to, we could develop it as a more CLIA approved sort of clinical actionable study test, but it’s not primetime yet.

So continuing on the topic of immunotherapy in squamous cell cancer. So 590 was a study that looked at Stage IV disease, predominantly squamous cell population, predominantly adenocarcinoma, predominantly esophageal cancer and some adenocarcinoma patients were included. So 590 is the way that we should not be doing studies anymore. It included both adeno and squamous cell histologies together. But it’s helpful to look at because there’s more long-term survival data. So it was a contemporary new study to CheckMate 649. So if you wanted to compare how does pembro versus nivo perform long-term, the answer is that they perform very similarly.

And this is an updated outcome data for both for overall survival and progression free survival population.

What about other immune checkpoint inhibitors, right? Should we bring in other inhibitors? Well we really don’t have a choice because the FDA doesn’t necessarily restrict if you have one inhibitor and you may not need another one. But if the study is designed to answer a specific question and if it meets its primary endpoint, it’s technically fair game for them to file for approval. And RATIONALE-305 tried to answer the question whether tislelizumab plus chemotherapy versus placebo plus chemotherapy can improve outcome in gastric and gastroesophageal adenocarcinoma. So very similar design to the other studies we just reviewed.

And once again, it’s nice to see the confirmation to show that both overall survival and progression free survival is improved. The degree of benefit appears to be identical. So it doesn’t really have a particular distinction from other inhibitors. And the question is, how will they pivot to have a foothold in the market? Hopefully perhaps with combination strategies, right? Because we know that combination therapies with either targeted or in other immune checkpoint blockade therapies will be helpful.

Similar also long-term follow-up for squamous cell, tislelizumab 2-year follow-up data was presented. And we see that it performs very similar to other inhibitors. Here, we can talk about difference of chemotherapy backbone for adeno — or squamous. In Asia, historically, taxane-based combinations are used. But in the United States, we use 5-FU/platinum, and most global studies do so.

DR LOVE: Before you get to that, I’m curious whether or not if we are able to develop larger trials or better ways of predicting benefit, do you think in the long-run we will see any difference between checkpoint inhibitors?

DR JANJIGIAN: Right.

DR LOVE: Any thoughts at a higher level about how this is going to eventually pan out?

DR JANJIGIAN: I agree with you, there is some data for negative studies for anti-PD-L1. So the question is, is anti-PD-1 and anti-PD-L1 different? Perhaps. I think we will hear more once MATTERHORN reads out because if MATTERHORN is positive and it’s anti-PD-L1, that’ll sort of negate that myth. But so far, the complete response rate with anti-PD-L1 versus anti-PD-1 is very similar in perioperative setting. Of course, DANTE used atezolizumab and that looked very similar.

DR LOVE: I always think about what happened in non-small cell lung cancer where durvalumab, they did the study, it was positive. The pembro study wasn’t positive, everybody uses durvalumab. So that’s all it seems to take.

DR JANJIGIAN: Yeah, exactly. And if the study is negative, we’re not going to do anything to resurrect it.

Speaking of combination strategies. So KEYNOTE-811 really was the first study in GI to be able to demonstrate a potential sort of strategy for dual tumor targeting with anti-PD-1. O I remember you interviewed me when the Phase II data came out and you were always very positive and supportive. And so we were able to demonstrate in second-line — in a Phase II setting in first-line, a dramatic improvement and then took it to Phase III. So the KEYNOTE-811 is a direct sort of result of a strategy and we demonstrated improvement in response rate. And as you recall, just based on the response rate, the FDA approved this as early sort of interim approval. And then recently, the FDA and EMA updated their recommendations. So we were able to present progression free survival of both in PD-L1 high or positive, CPS 1 in all-comers, and then progression free survival2 — or interim analysis, rather, second interim analysis. And third interim analysis, there is ongoing separation in the survival curves. And what’s interesting about this study is that the comparator arm, the standard of care arm has actually performed better than what we expected.

And you could ask me why that happened. But the idea is that over the years, the definition of HER2, what was used in the ToGA study which is compared to what is used now has changed. The ToGA study enrolled patients using mostly fluorescent in situ hybridization. And so patients with FISH-positive HER2-low IHC by IHC tumors were enrolled. And then this study used IHC 3+ or IHC 2+ and FISH-positive which is the CLIA approved method now. So what we demonstrated is that despite the fact that the control arm did quite well actually, we still beat it by improvement in progression free survival.

And the data that I think led to the EMA approval is this data even though it’s not final and will be updated. For CPS greater than 1, the overall survival, the median OS is 20 months versus 15.7 months. And this has not been sort of previously what you would expect, right? So in the ToGA study, the ToGA regimen, the median OS was about 14 months or so. So nice to see. We’re still waiting for the final OS. But because the progression free survival was a primary endpoint together with the OS, this regimen is now approved in Europe and United States and different parts of the world. We’re still waiting for the approval in Japan.

DR JANJIGIAN: So SKYSCRAPER-08 is a good one. It’s trying to answer whether or not we should be using TIGIT in combination with PD-1 in squamous cell cancer. And it’s a classic example of how a trial when it’s being designed is a great trial but now, it’s not that helpful because the comparator arm has changed.

So as you know, in squamous cell cancer, we use immunotherapy now in combination with chemotherapy typically or dual PD-1/CTLA-4 blockade. In this SKYSCRAPER-08 study, the comparator arm was chemotherapy with placebo. And once again, because it was predominantly a study enrolling patients in China, they used the taxane-based combination, so paclitaxel/cisplatin compared to, let’s say, 590, KEYNOTE-590 or CheckMate 648 where 5-FU/platinum is the backbone.

And this was a positive study. Definitely, you see clear separation in the survival curves. But is it any different than, let’s say, chemo/PD-1? I don’t know. Probably not at early look. But remember, TIGIT, at least in lung cancer and melanoma, you are going for the long game, right? Is it going to overall improve survival? Maybe, but we don’t know. Is it going to be better, not even overall? It will definitely improve survival compared to chemotherapy, but will it be better than chemoimmunotherapy? That’s the question. So it’s not practice changing, but kind of a cool study which just reaffirms that TIGIT is an interesting target. We certainly have, as you know, adenocarcinoma studies that are going to read out soon, but too soon to know.

Other Treatment Approaches for Gastroesophageal Cancers — Zev Wainberg, MD, MSc

DR WAINBERG: Hi. Good to see everybody again in this Year in Review comprehensive series. And I’m Dr Zev Wainberg from UCLA, and I do a lot of upper GI cancers, and I’m delighted to have this opportunity to present our 2023 Year in Review in gastroesophageal cancers.

So we’ll divide this into several sections. My topic will be some new drug development and some novel targets and see where we’re going in that direction but also to talk about some old targets like HER2 and fast-forward the field a little bit in the years to come, where we’ll be headed, and to touch on some other elements of refractory metastatic disease as well.

So we’ll begin with claudin 18.2 because we’ve known about this for about a year now, insofar as when I say known about this, I say we’ve known some of the clinical trials results of zolbetuximab in particular. But claudin 18.2, just a reminder, is a unique target that was first developed in gastric cancer, and we’ve known about for a decade now that it represents a novel target worthy of further discovery. And this was based on some earlier work done by a German biotech company that performed the trial called the FAST trial that demonstrated the addition of zolbetuximab to chemotherapy in patients preselected to have claudin 18.2-positive disease resulted in superior progression-free and overall survival. Now subsequent to that the increased development of that drug by a second company led to 2 large, randomized Phase III trials, both of which were presented and published in 2023.

Now a quick rehash of what is means, this target. This is not a typical oncogenic target. Claudin 18.2 is a tight junction protein that interlines the membrane and seals intracellular spaces and epithelia sheets of tissue, so it really doesn’t represent a typical target but rather represents an important protein in tight junctions. And it’s especially important because the presence of it in the normal human tissue is pretty much exclusively in the GI tract, and to be more specific in the upper GI tract, so that has very important implications on toxicity. And zolbetuximab is a monoclonal antibody that binds to that antigen and prevents its binding to the tumor cell.

So when the studies were first presented, as mentioned earlier, there was recognition that in an earlier Phase II study indeed there was benefit to adding zolbetuximab to chemotherapy for progression-free survival and overall survival. So in the year 2023 we saw 2 separate randomized Phase III trials taking zolbetuximab, adding it to chemotherapy, that both were done in the years preceding 2023.

First we saw something called the SPOTLIGHT trial, which was presented for the first time in GI ASCO 2023 and subsequently published shortly thereafter. And the second one was a study called GLOW, which instead of using FOLFOX as the backbone, which was done in the SPOTLIGHT trial, in GLOW they used CAPOX. Both of these were global/international, Phase III, randomized, placebo-controlled trials. And in both primary analyses of these studies the studies met their endpoints for both progression-free and overall survival as a key secondary endpoint.

So in the year 2023 we not only saw the primary publications of both these studies, but we also saw some longer-term follow up, which I’ll go over.

So the first one was presented with an additional 9.7 months of additional follow up. The reason that’s important is you start to see sometimes changes in the curves one way or the other. Here we saw no significant changes. We saw essentially a very, very similar result to what was presented in the primary manuscript.

Here we saw on this presentation that was done at ESMO GI — ESMO 2023, excuse me, that a group of patients who got zolbetuximab plus FOLFOX had an improved progression-free survival from 8.9 months to 11 months, so about nearly a 2 months in change improvement in PFS, which was statistically significant and was associated with a corresponding increase in overall survival as well. So really reproducing what we saw in the original data set and reaffirming what was suggested.

The key secondary endpoint is listed here on that publication and — on that presentation, excuse me. You can see it improved overall survival from 15.5 months to 18.2 months. So this is reassuring that with additional follow up you are seeing even better separation of the curves to some extent, and zolbetuximab plus FOLFOX did improve survival and PFS over FOLFOX plus placebo.

Not too different, we saw an additional 8.7 months presented in the GLOW trial. And again, not to belabor the point, but again here the backbone is CAPOX, so slightly different trial. Here we see a less — the median of survival here wasn’t as good, partially having to do with the global representation of this study. It enrolled less in Japan and Korea and more in China and in Westen world, and therefore the medians didn’t perform quite as well, but the hazard ratios were very similar in effect confirming the benefit of zolbetuximab plus CAPOX. So these 2 long-term follow ups really confirmed what in essence has a fairly complete package of zolbetuximab plus chemo in claudin 18.2 preselected patients.

Now when we compare these 2 trials side by side what we see is a remarkable similar pattern. Both have approximately the same impact in median progression-free survival and overall survival. Hazard ratios are very similar. Rates of nausea and vomiting, which are the significant toxicity associated with this drug and with this class of drugs, were very significant. And we’ll get into that in a minute because as these drugs eventually find their way into the clinic it’s going to be important to figure out how to manage this unique toxicity. But as you can see here if you line these 2 trials side by side we see fairly consistent results, which is of course reassuring.

Now, as zolbetuximab makes its way to FDA approval, I should point out that was expected earlier this month, but due to some possible manufacturing issues that approval has been delayed now, and we’re waiting to see when that drug is actually approved for use by the community. We are obviously in oncology interested in not just finding out ways to block claudin 18.2 in combination with chemotherapy, but other strategies. And here you can see here a synopsis of some of the strategies that have already been in development for some time. Some of those are starting to be presented publicly for the first time.

There’s even a CAR T-cell program which has been presented publicly and published showing that in select patients you can actually give cellular therapy for these patients. Sounds hard to believe, but this was a study done by CARsgen out of China, which demonstrated some efficacy in that group of patients. But the more practical ways that have developed include either bispecific antibodies using a second epitope and binding concurrently with claudin 18.2 or more commonly antibody-drug conjugates, of which we’ll present some data today, and there are many and many of these in development. For this unique group of patients, which probably represents 30-40% of metastatic gastric cancer and perhaps another 30-40% of metastatic pancreatic cancer, the pancreatic cancer studies are still ongoing at this time, but the early incidence suggests it could be up to 30% to 40% of patients.

So this was the largest study presented to date with a claudin 18.2 ADC, and this trial, which is called KYM901 study design. And there have been a few of these out there, so I just selected the one that has the largest data set. And this was an ASCO Plenary Session in November 2023 I believe.

And this study enrolled patients who had previously received standard of care who were either claudin selected or unselected in their dose escalation, and then in the expansion claudin selected only. So what they presented here was data on 113 patients with refractory gastric or gastroesophageal junction cancer who were treated in various cohorts with this antibody-drug conjugate. And you can see the results were pretty impressive, I think, with respect to response rates, which again was the primary endpoint of the study. Response rate being by RECIST of course. You can see that the groups of patients that had responders varied depending on what dose was received and depending on whether claudin 18.2 was positive or not. But there’s certainly the suggestion that in the preselected patients who were claudin 18.2 positive we’re seeing response rates in the 40% range at the doses that were ultimately taken forward in the clinic.

So this study’s now moving to a larger phase study in patients with metastatic gastric cancer who are also claudin 18.2 positive, as are other drugs that brought claudin 18.2 in other ways, such as bispecific antibodies or even more potent and selective antibodies with chemotherapy. So this has led to an explosion of drug development, particularly in Southeast Asia, but also in the Western world as well, to find the best way to block this target in this select group of patients.

Now one of the challenges has been biomarker overlap. And we already know, and this has been a huge interest for many of us in this field, and a number of us are involved in trying to study this area as meticulously as we can, but we’ve seen from the GLOW and SPOTLIGHT studies that we’re probably looking at about 30% of those patients, ballpark, are CPS greater than 5. So about 30% of those patients are PD-L1 sufficiently high that we would expect benefit from a checkpoint inhibitor with chemo.

So the studies, though, have not been done with checkpoint inhibitors yet. And so what we’re seeing is okay, if we have 30% who are claudin 18.2 positive and CPS positive, number 1, what drug should we use? Number 2, can we combine these agents together with chemotherapy? So we really don’t know the answer to that question. That’s still left to be determined.

The ILLUSTRO trial, which is a trial that’s ongoing now, a single-arm Phase II study designed to show at least safety with the combination of FOLFOX or CAPOX plus zolbetuximab plus nivolumab, is enrolling now. And at least insofar as early indications far as safety’s concerned it seems to be safe. The question is how are we going to determine if it’s efficacious. Is it going to require randomized Phase III studies. These are all subjects that we don’t know the answers to at this time.

So one of the big things that, as I mentioned, when we’re talking about claudin 18.2 targeting is toxicity. I think people in the community will be a little surprised by what they started to see here. And what we have to recognize is that there are certain challenges when we’re developing new drugs like this that have unexpected on-target toxicity, and what I mean by that is the normal stomach mucosa is loaded with claudin 18.2-positive cells. So as we block that with any mechanistic drug we would expect local toxicities, and that’s indeed what we see here.

So nausea and vomiting is reported with all of these drugs. There’s not any drug so far that hasn’t reported some nausea and vomiting. They vary with respect to intensity of it and how to manage it, but it’s clear that the class effect is there. The other thing that seems clear is that there’s tachyphylaxis that seems to develop, and what I mean by that is that the first dose is the worst, and subsequent doses induce less nausea and vomiting on average. So there is something to be said about coaching the patients to assure them that while the first dose may cause this symptom if managed properly on subsequent doses that toxicity will diminish.

It's not a centrally induced nausea/vomiting. So the way we typically manage these things with ondansetron and 5HT3 blockers or other antiemetics are less effective in fact. What’s been shown to be the most effective in a number of studies now has been a few simple things. One is slowing the infusion time. The speed with which the infusion times seems to impact the degree of nausea and vomiting. So slowing it down, whether it’s the standard of care zolbetuximab, which hopefully will be available in the next 6 months, or study drug, slowing the infusion time could go a long way to making patients have diminished nausea and vomiting.

We are investigating the roles of both premedicating with dexamethasone and premedicating with H1/H2 blockers like diphenhydramine or even other H2 blockers. And what we’re figuring out as we go is that some of those may seem to help as well.

Lorazepam is also not a bad idea for a lot of patients who have anticipatory nausea and vomiting. I’ve used that a fair amount, although what I’ve found is the most essential is critically addressing both the prophylaxis part of it and also the management.

DR LOVE: I’m just curious. Roughly how many times you yourself have used zolbetuximab. And can you kind of give me a little bit more of a qualitative description of what actually happens when you start to see it and what — if you slow the infusion time down how long does it take before they feel better? Just a little more about what you actually see.

DR WAINBERG: Yeah. Yeah. Good question, Neil. I mean zolbetuximab in particular probably under 10 times myself, but claudin 18.2 targeting agents close to 50, 60 patients, because we have many trials with these other drugs. And I think it’s fairly reproducible. What happens with zolbetuximab is basically happening with the other antibodies and with the ADCs as well. It’s really a class effect.

Now to be granular about this, which is very important, it can happen in the chair. So I’ve seen a number of patients start to get nauseous in the chair, and that’s despite giving them premedication in all the ways we’ve discussed. And so that’s what I mean by slowing down the infusion time because if you slow down that infusion time, let’s say the package says give it over 2 hours, and you give it over 4 hours, that’s very — that makes a big difference.

What it does set up, though, are unique challenges in how we’re going to dose this drug with FOLFOX. So this is going to be a lot of trial and error. In practice what I’ve done in some patients is I’ve given it the next day sometimes. If they’re getting FOLFOX on day, if it’s too long a day, get the zolbetuximab on day 2. I don’t think there’s something wrong with that, and in fact I think it’s a more practical way because it’s going to take 4 hours of just the drug in a lot of patients, and that adds a lot of chair time to what is already a busy day.

So those are some of the practical tricks. It’s also managing the nausea. If it happens what do you do? And if it happens we slow down the infusion, we give extra premedication and a lot of times there I’ll throw in, if I haven’t yet already, lorazepam, and I.V. hydration, and coax them through it. But it is a period of time, and I think there’s going to be some experience that we gain in the community once this drug becomes available.

DR LOVE: — you’re describing it maybe also stop and think a little bit about what other situations do we see in medicine where we have nausea and vomiting that’s a direct effect on the stomach. For example, when you get like food poisoning. Is that what’s going on, or is it central? And like what works for that kind of nausea and vomiting?

DR WAINBERG: So that’s the challenge. I think central nausea and vomiting is very different than local nausea and vomiting, and maybe it is more akin to food poisoning, where it’s direct toxin damage into the stomach lining.

I’ve had experience with all of the antiemetics, and that includes some of the fancy ones, like the patches, the 3-day things. And a lot of them work a little bit, but they don’t work as well in this drug as they do on cisplatin for example.

DR LOVE: Right.

DR WAINBERG: They don’t work as well in this drug as they do in standard cytotoxic chemotherapy.

For this drug what works the best, in my experience so far at least, a number of us, I think, share this experience, is fluids, slowing down infusion rates, extra medications like maybe H1/H2 blockers, and/or lorazepam to decrease both some of the anticipatory nausea, which will certainly be there for their second cycle, and some of the perhaps direct effects of the antibody on the target.

DR LOVE: I mean I can’t think of any drug that has this story. No. Ever since I’ve first heard about this I’m like — yeah, no. I think it’s — I hope it doesn’t scare people away. That’s what I’m thinking. Sometimes new agents come in, people try it once, they have a bad experience, they don’t do it again, and I just hope that doesn’t happen here. But really, they’ve got to really be thinking about this.

DR WAINBERG: I’m sure they are, and I mean I think everybody who’s been involved in these programs the last year has advised all of the drug development side on this — do not take this lightly and think about how the community oncologists are going to be dealing with this in busy practices who don’t have hundreds of gastric cancer patients so your first experience with it is sometimes lasting. So I completely agree. I can’t think of another circumstance quite like this, but I’m told there are some in some rarer cancers.

DR LOVE: Incidentally, I was flipping through the ASCO plenaries looking for the thing, and I saw there was 1 coming up, fruquintinib and paclitaxel second line. Do you know about that?

DR WAINBERG: That’s second-line gastric.

I hadn’t heard the results were already available.

DR LOVE: Yeah. I mean fruquintinib sounds pretty good in colon to me. I mean it’s not like great, but maybe it’s going to be better than regorafenib, so I don’t know.

DR WAINBERG: Yeah. I mean in this context I imagine they want to replace ramucirumab, which is already approved with paclitaxel in second-line gastric. So yeah, I’ll be curious to see that result. It certainly does look like a gentler version of regorafenib.

DR LOVE: Yeah, but I mean I would assume it’s not any easier than ramucirumab.

DR WAINBERG: Probably not because kinase inhibitors are sometimes trickier to combine with chemo, as you know.

DR LOVE: Yeah. One other thing though I was going to ask you, speaking of that. So you’re saying the ADCs also cause nausea and vomiting? Because somehow I would think it would be a lower dose, but maybe not. I don’t know. Is it?

DR WAINBERG: No, because the dose of the antibody in the ADC is basically the same dose, more or less, as you get with the naked antibody. I think the advantage of an ADC in a disease like gastric cancer is that if you can combine it with less chemo as a single agent it might have some activity. You don’t necessarily need all that chemo.

The antibodies, it’s an interesting point that you make, because zolbetuximab, and this is also in the ILLUSTRA study that was just published by Dr Klempner and colleagues, there was no activity of the single-agent zolbetuximab. The antibody itself, despite blocking claudin 18.2, has no activity as measured by response rate, and zolbetuximab plus chemo doesn’t increase response rate over chemotherapy alone. So the principle is the antibody-drug conjugate will actually induce a response rate, which as you saw in that presentation from the Chinese group has already demonstrated that it does. And it will essentially replace the chemo/zolbetuximab combinations once it’s further developed.

DR LOVE: Right yeah. I guess the thing with ADCs is you have less of the payload but not less of the target, the way you’re describing it.

DR WAINBERG: It depends. There’s usually a DAR, so a drug/antibody ratio, and it varies between ADC and ADC, but you don’t always have a different antibody potency certainly. And at least in most of the clinical trials presented to date the degree of nausea/vomiting that were seen with these ADCs is very, very similar to what we’re seeing with the antibody/chemo combinations.

DR LOVE: Really? Wow. That is interesting. All right. Please continue.

DR WAINBERG: All right. So switching gears from claudin 18.2 to an older friend of ours, HER2, and the results, the final results of the KEYNOTE-811 were recently presented at ESMO 2023 and simultaneously published in The Lancet by Dr Janjigian. And this study was one of the largest done to date in HER2-positive metastatic gastric cancer. We had seen in the past response rate data showing that it improved response rate by about 25% compared to chemotherapy plus trastuzumab, and what I mean is the investigational arm, chemotherapy/trastuzumab/pembrolizumab, had improved response rate by 25% over chemotherapy/trastuzumab.

So here what they did is show us the interim and final progression-free survival information. So this took patients who were newly diagnosed HER2 positive, randomized them 1:1 to either chemotherapy plus trastuzumab, and here it was CAPOX chemotherapy by the way, versus chemotherapy/trastuzumab plus pembrolizumab. Primary endpoint was overall survival and progression-free survival.

Now after 38.5 months of follow up, very long follow up here, the progression-free survival at interim analysis 3 was presented, which is what we’ve been waiting for here, and this showed that there was a statistically significant improvement of progression-free survival from 8.1 months to 10 months, which was hazard ratio of 0.73. If one took out the small group of patients who were CPS less than 1, and that’s about 15% of the HER2-positive patients, the hazard ratio gets slightly better to 0.71. So what we see here is that, again, the 85% of patients who are CPS greater than 1 and HER2 drive most of the benefits of this agent.

Now when we looked at overall survival, which was also presented and published by Dr Janjigian in The Lancet, the statistics were not quite as statistically significant. As you can see, the hazard ratio’s 0.84, and it does cross 1.01. The curves tend to come together there. The CPS greater than 1 curve we’re still waiting to see if it’ll meet statistical significance. Obviously you can see at the bottom of the curves they start to come together.

Now what this has meant in practice is that the FDA modified the existing label. Before it had accelerated approval. Now it has a bigger approval, but its approval consists of patients with CPS greater than 1. So moving forward for patients HER2 positive, CPS greater than 1, those patients are receiving chemotherapy/trastuzumab plus pembrolizumab.

There’s been some degree of extrapolation of this data from CAPOX to FOLFOX as well, but that’s been a change in 2023. And technically speaking if your CPS is less than 1 and being HER2 positive you no longer have this drug approved, and the question is what should you do with that patient.

Now in HER2-positive disease the story doesn’t end there because that’s front line. And now we’ve seen there’s a few new drugs, and I’ll mention a couple of these now. Zanidatamab is a bispecific HER2 targeted antibody. It doesn’t block 2 different antigens. It just blocks 2 different extracellular domains within HER2. Here it’s blocking ACD4 and ADC2. And this drug’s focused on a few cancers, particularly in the GI tract.

Now there have been some Phase I studies that have been presented and published with this drug, and what’s interesting here is that this drug, as opposed to trastuzumab, has single-agent activity even in GI cancers that are HER2 amplified and HER2 positive, so there’s some excitement about that, and certainly a good amount of activity when combined with chemotherapy.

Now that led to a Phase II study of sorts that looked at zanidatamab plus chemotherapy and showed some encouraging response rate data. As you can see here in this waterfall plot very, very high response rates, a lot of them were confirmed, and that led ultimately to a Phase III trial.

The Phase III trial was called HERIZON-GEA-01. It’s a 3-arm trial, interestingly. Remember, this trial was launched a couple years ago, so before the KEYNOTE-811 regimen had been approved by the FDA. So this trial was taking newly diagnosed HER2-positive gastric cancer patients, randomizing them to 1 of 3 arms, either a CAPOX plus trastuzumab arm, which again was the standard of care up until 2 years ago, or to the chemo plus zanidatamab arm, so just this presumably better trastuzumab version which blocks 2 elements of HER2, or a third arm which combines the zanidatamab plus chemo plus tislelizumab, which is again a PD-L1 antibody as we all know. So this study is enrolling quite rapidly, and the expectation is we’ll get a result sometime next year.

This raises the question of course of if the — what will be the contribution of components, which essentially is why the FDA required this 3-arm study. So we’ll wait to see what the results are probably in the year to come to see whether this will present an opportunity even for the CPS lower patients to get some drug approved for that situation.

DR LOVE: What do you see tolerability wise with this? This is a bispecific. Do you see heart damage or any other issues?

DR WAINBERG: So far what’s been reported has been that the toxicity of this drug is pretty well — it’s a well-tolerated drug. I think it’s not that much more difficult than trastuzumab. It does cause some GI toxicity; a little more than trastuzumab does. I don’t think there’s an increased risk of cardiac issues beyond trastuzumab as a single agent. There’s no unique toxicities here that are different from a little bit of GI and the typical HER2 blockade toxicities. So overall pretty well tolerated. 

So moving on to HER2 and antibody-drug conjugates. Again, we’ve seen that there’s a role of T-DXd, which we’re all familiar with from both breast cancer and other cancers, colon, lung. We know there’s a lot of data with this drug now across the board. We know about this antibody-drug conjugate. We know that it has unique activity but also unique side effects.

There was a final publication in 2023 of the DESTINY-Gastric02 study, which enrolled patients in the Western world who were confirmed to be HER2 positive with a biopsy on enrollment that was mandatory and confirmed to be HER2 positive before enrollment. And these patients were treated with single-agent T-DXd at 6.4 mg/kg. 79 patients. The idea was to try to reproduce the results from our Asian colleagues that had published DESTINY-Gastric01.

And the upshot of it is as of the publication by Dr Van Cutsem earlier this year the response rate was 42% confirmed. This included a few CRs even, and a duration of response of 8.1 months with a median PFS of 5.5 months, and an overall survival of 12 months. So pretty close to what the DESTINY-Gastric01 study showed insofar as response rate and reaffirming, I think, the suggestion that it works in patients from the Western world as well and got ultimately approved for that context based on this companion study to the DESTINY-Gastric01 study.

Now the questions that have come up in HER2-positive disease, just to start at the top again, the KEYNOTE-811 is now approved for HER2- and PD-L1-positive patients only.

DS8201, or T-DXd, is approved for second line and beyond HER2-positive gastric cancer. Now we await the randomized trial, that hasn’t been done yet in second line, and that’s called the DESTINY-Gastric04 study, and that’s randomizing patients to T-DXd, to paclitaxel/ramucirumab, which is the standard second-line therapy for even HER2-positive gastric cancer. That trial’s ongoing. We might see results next year.

There is still this issue of pneumonitis, which is a black box warning on T-DXd. And a number of other studies, Neil, have suggested that 5.4 is an adequate dose in colon cancer, and so the question is should it be utilized here as well. And I think we haven’t done the study in gastric cancer but gosh they published a study last year at ASCO, Dr Raghav, that 5.4 was just as good as 6.4 and was less toxic. So I tend to think the same concept might be applicable here quite frankly, and that’s how I’ve utilized the drug in practice.

Zanidatamab looks promising. I think we have single-agent activity here, and we’ll see if the results come out in 2025.

Now future directions for HER2 are there’s still room to grow here. It represents 25, 30% of patients, but the question is, is this HER2 low thing that’s been such a big story in breast cancer, is that applicable here in gastric cancer. So far all we’ve got to say about that is that Yamaguchi published in an Asian cohort last year that they have a response rate of about 26% in HER2 2+, 9% in 1+. But it only had about 20, 25 patients in each cohort, so really the numbers aren’t huge here. That’s being explored further both in an Asian cohort of patients and in a cooperative group study in the United States trying to look at increasing that HER2-low group, which again could theoretically represent another 20 to 25% of patients or even more. So that’s going to be the subject of a huge amount of interest in the next couple years.

Synchronously with that people are looking at ctDNA as a predictor. There have been a few abstracts presented this year that have suggested that what we thought we knew, which is that sensitivity of circulating tumor DNA, of HER2 in particular in liquid biopsies, is very high and can be utilized in the context of patients who progress on HER2 therapy to ensure they’re still HER2 positive or even in the beginning if there’s inadequate tissue available, that it’s sufficiently sensitive and specific for HER2 in this group of patients. So HER2 remains an area of active interest in gastric cancer.

What we haven’t seen yet, which we might see in the next few years, is a reboot of the possible adjuvant therapy options in HER2-positive. We’ve been still lingering on that one relative to breast cancer because of some negative studies, but we may now see a resurgence of interest in looking at HER2 in both the neoadjuvant and adjuvant context in gastric cancer.

Now when it comes to refractory disease I think we’re still dealing with some clinical realities, which is that the disease tends to progress very quickly. We are seeing more patients present to third line and that becoming a more feasible option. We tend to utilize a lot of FOLFIRI. There was a publication earlier this year from the Germans that showed that FOLFIRI/ramucirumab is an effective option. We’ve known about that for some time, but they did some randomized data showing — randomized studies showing it compares reasonably well with paclitaxel/ramucirumab, so that could be considered.

There was a JCOG study that was presented, not published, earlier this year that suggested that if you get paclitaxel/ramucirumab, there wasn’t a lot of bang for your buck out of FOLFIRI/ramucirumab, so maybe this VEGF beyond progression doesn’t apply here I this disease. That may be what that study would indicate. We haven’t seen the full details of that yet.

And of course we’ve got TAS-102, which has been approved now for a couple years in refractory situations.

We are seeing though interest in more companies now in refractory gastric cancer. There’s a big program in TROP2 ADCs which is about to launch, along with B7H4 ADCs, which represent 2 reasonable targets where antibody-drug conjugates have activity in other cancers that we’re hoping extrapolates here.

I think the field of ADCs in GI cancers is growing every meeting, and so we can expect that certainly in a disease like gastric cancer where the concept of having a payload is critical hopefully we will be able to show more and more data to that effect in the next few years.