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The Role of Checkpoint Inhibitors in Gastric Cancer

— Ghassan Abou-Alfa, MD, leads a discussion with Anthony El-Khoueiry, MD, and Steven Maron, MD, MSc

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In this exclusive roundtable video from 鶹ý, three expert leaders in the field of gastrointestinal cancer discuss the latest emerging data presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Moderator , of Memorial Sloan Kettering (MSK) Cancer Center in New York City, is joined by , of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, and , also of MSK, in this second of four episodes, in which they discuss the clinical impact of the and studies.

Following is a transcript of their remarks:

Abou-Alfa: Well, hello everybody, and great seeing you again. And whoa, we are still kind of wrapping up from GI ASCO, and it's still going on with a lot of information that we thought, why not have a roundtable and discuss some of the new things that were evolving. We learned from each other, a lot of things that we learned and a lot of things that we reflected on.

So, as you know, my name is Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center in New York. And today I would like to welcome my two dear colleagues, Dr. Anthony El-Khoueiry from the University of Southern California Norris Cancer Center, and Dr. Steve Maron, dear colleague, also from Memorial Sloan Kettering Cancer Center in New York.

So I have to tell you that historically, gastric cancer is a chemotherapy-based therapy treatment, but at the same time there's so much advance we hear about, and we heard quite a bit about things in GI ASCO, among which is the checkpoint inhibitors, there was something on tislelizumab, there is also all what's regarding the HER2 receptors and expression of them.

So please tell us in a nutshell, what really caught your eye mostly at GI ASCO?

Maron: I think what really sticks out from GI ASCO is that we now have phase III data from the double-blinded placebo controlled study, it's called SPOTLIGHT, and so this taking chemotherapy combined with zolbetuximab or placebo, and building around the data from the FAST trial.

Now the phase II FAST trial run by the Germans was so long ago now, it was presented in 2016 at ASCO. It was EOX [epirubicin, oxaliplatin, capecitabine (Xeloda)] plus zolbetuximab or placebo, and they had positive data events. So we've been really excited about Claudin. And so we now have in this population of patients who have very high Claudin expression, so at least 75% of their cells with 2-3+ expression, represents actually almost 40% of the esophagogastric cancer population -- so a huge population that'll benefit. And what they showed in this study was that they were able to improve both progression-free and overall survival with the addition of zolbetuximab to chemotherapy.

There are a couple important caveats though that we saw. One was, interestingly, that there was no objective response benefit despite seeing both a progression-free and overall survival benefit. And two, I actually thought this was the most interesting, if you look back to FAST, the overall survival in the placebo arm was actually a median overall survival that was double that of FAST. And so both arms really just did so much better than they did 6 or 7 years ago now.

And then the last caveat is that this was without concurrent PD-1 therapy, which was also discussed at GI ASCO with the updated results from CheckMate 649. And so this question that really burns in I think everyone's minds is: Now with the zolbetuximab data that's positive, with more positive data announced from (not yet presented using CAPOX instead of FOLFOX), who are the patients that we're going to add zolbetuximab to first-line therapy for when I expect the FDA will approve this later this year?

Abou-Alfa: I like very much what you said and a reminder, correct me if I'm wrong, in regard to the zolbetuximab, which as you said, it was a late-breaking abstract, the patient had to be Claudin 18.2 positive and HER2-negative. Am I right about that?

Maron: You're absolutely right. And very positive.

Abou-Alfa: Very.

Maron: So we're still discussing PD-L1 expression and what cutoff to use, using a cutoff of 1%, of 5%, of 10%, you actually need a 75% expression cutoff [of Claudin 18.2] to get into this SPOTLIGHT study that's presented, which is unheard of in this cancer.

Abou-Alfa: Interesting. And along that line, please, can you tell our colleagues, Claudin 18.2 -- HER2 maybe we're a little bit more used to -- but Claudin 18.2 -- how do I test for these things? What's required of me to make sure that patients are yes\no.

Maron: We actually don't have an approved companion biomarker yet.

Abou-Alfa: OK.

Maron: So when this is approved, it'll be the first approval for a Claudin 18.2 inhibitor. And so with it we will have Astellas' companion biomarker, presumably, and then the pathologist will need to really learn how to identify that cutoff of 75%, which is no easy task. Right?

Abou-Alfa: Absolutely.

Maron: And the question is, with each and every drug that we have targeting Claudin 18.2, what antibody to use, what cutoff to use.

Abou-Alfa: That's very helpful. And tell us along that line, it seems that -- correct me if I'm wrong -- you get a little of ease regard to HER2 based on that data, but maybe something else. Where does HER2 come into play in regard to the disease?

Maron: Yeah, so HER2 , we have about 15% to 20% of patients who are clinically HER2-positive, so 3+ or 2+ and ISH [in situ hybridization] positive. And for these patients now, the progression-free and overall survival is just exponentially increased almost it seems with KEYNOTE-811 now leading to the approval of adding pembrolizumab [Keytruda] based on objective response in the interim analysis. We're still waiting on the progression-free and overall survival from KEYNOTE-811 to read out. But we're already using this in the U.S. and approval is pending around the world as well. Even more recently, we also have this approval for trastuzumab deruxtecan [Enhertu] in the second- or later-line based on recent data from DESTINY-Gastric01 and DESTINY-Gastric02. And the data, it's almost the same from the east and west experiences in 01 and 02, which is really not something we often see, but it's nice to see when the data is recapitulated.

Abou-Alfa: So again, in summary, 15% or so, and it's more second-line at the moment until we wait for more data in regard to the outcome in this first-line, per se.

With this said, you already alluded to the checkpoint inhibitor, so maybe you can go back to this. What is the role of checkpoint inhibitors in gastric cancers?

Maron: Great question, Ghassan. CheckMate 649 presented by Dr. [Yelena] Janjigian, and also from MSK, updated data now at 3 years showing that we're still seeing this progression-free and overall survival benefit, both in the overall population regardless of PD-L1 expression, but most profoundly in those who have a PD-L1 CPS [combined positive score] score of 5 or greater.

And the real question, and if you look at the guidelines, it's really quite complicated how it's broken down for category one, two recommendations. It's really a question of what to do with patients who have a PD-L1 CPS of less than 5. Five-plus, very clear benefit, [microsatellite instability] MSI-high, even more profound benefit. But in our practice, there's some variability in terms of if somebody has CPS less than 1, do they benefit? Probably not per the data presented at GI ASCO. In the 1-4 mark, likely some patients that are benefiting, but it's not a statistically significant benefit for these patients. Part of that is due to the interpretation by the pathologist. Part of it is due to staining, and it's certainly heterogeneous. So it's a remaining question.

Abou-Alfa: And along that line, from the practical standpoint, Steve, do you think the CPS scoring would require a second opinion to pathology? How experienced are you seeing for example, do you receive reports from the outside from the community that you wonder a little bit about the CPS scoring? How experienced are our pathologists across the country?

Maron: I wonder a lot. I'm seeing TPS [tumor proportion score] scoring and CPS scoring, I'm seeing differences from one sample to another collected at the same time. At the end of the day, any pathologist you talk to will say there will be variability. We are overthinking a very modest biomarker that has an excellent negative predictive value, but not a very good positive predictive value, and we need better biomarkers.

And so in my practice, if it's a CPS of less than 1, I don't generally offer PD-1 inhibition unless it's part of a clinical trial with an additional agent, which we'll get to with in a moment. And then if it's 1-4, I have a risk-benefit discussion with the patient, I think there's a low likelihood of benefit from it. If there's a trial available, I think it's a great idea, but if mentally they're going to sleep better at night knowing that they're receiving immunotherapy, I would not withhold this FDA-approved drug.

Abou-Alfa: I like that. And this is very important for our colleagues to integrate. I appreciate, It's not like we're questioning the qualification, but these are like all new stuff. And maybe here, this is really the role of the medical oncologist. If they're really not sure, and they are questioning exactly as you said -- less than 1% is a zero, you got it. But in other words, if it's really iffy and there's a question, maybe seeking another opinion for the pathology is not a bad idea either. I totally agree with you.

Watch episode one: Two Biliary Tract Cancer Trials Took Center Stage at ASCO GI

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.