DR LOVE: Welcome to Oncology Today — Highlights from the ASCO and ESMO 2020 meetings in gastrointestinal cancers, I’m medical oncologist Dr Neil Love. For this podcast, I met with Dr Philip A Philip from the Karmanos Cancer Institute in Detroit, Michigan for a mini-journal club to discuss some recent presentations from ASCO and ESMO in gastrointestinal cancers that were most likely to have an impact on clinical practice. To begin, he talked about his ASCO presentation on targetable alterations in KRAS wild-type pancreatic cancer.

DR PHILIP: So I’m going to start with the study that we presented in ASCO.

DR PHILIP: So, for the study that we did was based on patients who had undergone next-generation sequencing, and this is a study which is alterations in the targetable molecular pathways enriched in KRAS wild-type. So, the message from this study was, if you have patients with KRAS wild-type, then you have opportunities in terms of targetable molecules. And even immunotherapy might be a bit more of a chance here then. But the key thing is that in RAS wild-type, there are some possibilities of very good targetable mutations. NRG1, BRAF fusions, ROS1 fusion and several, ALK mutations. So, really, that's an opportunity I think for a patient to have in terms of treatment options.

DR LOVE: So, what percent of pancreatic cancer is KRAS wild-type?

DR PHILIP: Approximately 10%.

DR LOVE: Ten percent, hmm. What’s the practical implication of this? I guess, typically would you know the KRAS status without getting NGS?

DR PHILIP: You can do it on the sample. I mean here the point I’m trying to make is that just checking for it. I mean the study was based on NGS, but you can check the KRAS mutation very easily in the hospital, like it was being done for a long time for our patients with colorectal cancer. So you can get a KRAS mutation, yes. And what happens, if you get the KRAS mutation and it's wild type, then you can do the rest of the testing here.

DR LOVE: Right. Right. So, have you had any patients who got targeted therapy and responded with pancreatic cancer?

DR PHILIP: We had patients, NTRK mutation, we had one patient. We had a patient with ALK mutation. And they get response, but they’re not as good as you see, for example, in patients who have lung cancer, for the ALK mutation. But, still, is an opportunity for the patient to be stable for 4, 5, 6 months on the treatment. I personally, I haven’t seen a patient with an NRG1 mutation, but that could be another interesting to have.

So, these are patients who have no other options, you have to remember. And all it takes is checking for the KRAS. If it's mutated, that's it. If it's wild type, then that's where the thing comes.

DR LOVE: How about this other ASCO paper, SWOG 1515?

DR PHILIP: So the SWOG 1515, you can think of it in one way, and that was the first head-to-head comparison of gemcitabine/nab paclitaxel and FOLFIRINOX. Although, it was in the metastatic disease, it was in localized disease, resectable disease. And in that trial, really the take-home message was they're both similar. So that was the major take-home message, that both are similar in terms of activity and are comparable in terms of toxicity.

DR LOVE: I think that FOLFIRINOX has, in general, been the standard of care in terms of potentially resectable disease. I mean it's been thought to be preferred. Do you think will change anybody’s mind?

DR PHILIP: It's changing mind and also changing practice, which sometimes is more difficult. I think it will increase the use of gemcitabine/nab paclitaxel, especially in patients who may not be that great in terms of their performance status or age or something like that. Now people have less concern about not using FOLFIRNOX. I think in that sense it will.

DR LOVE: And I guess this still means you wouldn’t use it in the adjuvant situation?

DR PHILIP: Not in the adjuvant situation. No.

DR LOVE: So do you want to go through some ESMO papers?

DR PHILIP: So the study, a small trial of 77 patients, using avelumab plus cetuximab in patients with RAS wild-type who’ve been previously treated with EGFR inhibitors, metastatic colorectal cancer and then rechallenged them again now using cetuximab plus the immune checkpoint inhibitor. And there was some activity.

So this goes into what people are trying to use in patients who have microsatellite stable, people are trying to find combinations to use. And here, in fact it's going back to using the EGFR blocker plus immunotherapy. A small study. But certainly something to keep in mind in someone who may need a rechallenge.

DR LOVE: What’s the thinking of the synergy or why it would work?

DR PHILIP: I don’t have a real easy explanation, except for what they were saying, that the cetuximab enhances the antibody-dependent cell toxicity and increases the expression of MHC+2 molecular on the dendritic cell. So that would be my only thing, which is they’re claiming, which could be the case. I don’t know.

DR LOVE: What about this KEYNOTE 590 study?

DR PHILIP: So this is interesting because this is pembro, and they used it with cisplatin/5-FU because this study was being done mostly in Asia — including Asia.

And remember the KEYNOTE 062 in the frontline setting, adding pembro to chemotherapy did not really help. But here, they're not doing it in gastric, they’re doing in esophageal and also in GE Junction adenocarcinomas. And in esophageal, they’re also including squamous cell.

The bottom line is that the combination resulted in improved progression-free survival. And the question is, is this really going to be the standard of care now. And if you look at the different categories or subgrouping squamous cell, squamous cell with CPS greater than 10 and all that, so there was interesting improvement and the hazard ratios were really worthwhile. So, basically, a PFS improvement and also OS improvement.

The way I concluded on this trial number one, squamous cell responds better than adenocarcinoma. I think people tend to believe that. And the second thing is that you need a good CPS score. And to get a good mileage for your immunotherapy, at least with the pembro which is linked to a biomarker, you have to use probably 10 cutoff.

DR LOVE: That's interesting.

I don’t know if other people kind of get confused between esophageal cancer and gastric cancer. I mean that's a pretty basic question. It's easy to say squamous and adeno.

How do you conceptually think about esophageal cancer and gastric cancer?

DR PHILIP: Esophageal, you have the squamous which is what you and I learned when we were in medical school. It is in the middle part of the esophagus linked to smoking. That was a risk factor. And then you have the lower part of the esophagus adenocarcinoma, which is where most of the action is, in the Western world at least, related to obesity and the GERD. And then you have the GE junction, which is related maybe a bit more to esophageal adenocarcinoma, but it’s right in the middle. And then you have the gastric adenocarcinoma.

So I think it’s pretty well delineated, except for the GE junction, which, in clinical trials sometimes it’s included with gastric, sometimes included with esophageal adenocarcinoma.

DR LOVE: What about adeno of the esophagus? How do you treat them?

DR PHILIP: Yeah, I think when you talk about metastatic disease, you’re treating them more like gastric adenocarcinomas.

DR LOVE: Right.

DR PHILIP: So I treat metastatic — so gastric adenocarcinoma, GE junction adenocarcinoma, esophageal adenocarcinoma, at this point in time the treatments are pretty much similar, if not the same.

DR LOVE: But adenocarcinoma of the esophagus. You treat it like gastric or you treat it like esophageal?

DR PHILIP: No, gastric. I treat like gastric. So, again, it depends what you mean by treatment. If you’re talking about metastatic disease, I will use frontline FOLFOX, second line paclitaxel/ramucirumab, third line, whatever. I will use the similar thing. For the squamous cell it’s different.

DR LOVE: So, what do you do with squamous cell?

DR PHILIP: So, squamous cell, like frontline, you use also like FOLFOX

 But once you hit the second line, you can use irinotecan-based treatment, but the ramucirumab and paclitaxel, that’s an adenocarcinoma study, didn’t include squamous cell in it.

DR LOVE: Right. And the other question is what’s your bar to bring in a checkpoint inhibitor, esophageal versus gastric?

DR PHILIP: So, basically, if I want to use a immune checkpoint inhibitor, if I’m in the third line of esophageal adenocarcinoma or even gastric or esophageal adenocarcinoma, if I’m in the third line, as you know, you can use nivolumab even without having a CPS score, or I would use pembrolizumab with a CPS score that is 1 or more.

I mean the confusion is that the nivolumab and pembrolizumab have been developed in a way one is linked to the biomarker with its FDA approval and one is not. That really creates confusion. And I think, at least for the insurance purposes maybe, if you’re using pembrolizumab in someone who has zero expression, you may not be able to give pembrolizumab, but you can give nivolumab.

In patients who have squamous cell, the FDA, as you know, has approved the KEYNOTE 180, has approved pembrolizumab with a CPS score of 10, even in the second line. As I said, because there’s nothing good in second-line squamous cell.

DR LOVE: Okay. What about this cholangiocarcinoma FGFR fusion, this study.

DR PHILIP: Yes. So, basically, the message here is that you really have to test those patients because FGFR mutations are real. They’re like 15% or so of the patients with cholangiocarcinoma. They’re common, in a sense. So to start off with, half of the patients almost with cholangiocarcinoma can have a targetable mutation. You have the IDH1, as you know, FGFR, HER2, MSI, etc. And basically, you need testing. And also, the fact is that there are a number of drugs that are being developed for this and this is one of the drugs, futibatinib. It's more as something to remind people that these drugs exist and there are more than one. And I think at the end of the day, you’ll end up with multiple of these available in the market.

DR LOVE: And the responses are kind of typical targeted type responses? Most people respond.

DR PHILIP: Yes.

DR LOVE: And it lasts for a while?

DR PHILIP: Yeah.

DR LOVE: Interesting. What about the paper on NTRK fusions in biliopancreatic cancer?

DR PHILIP: Again, that's on the same line that if you do your NGS, looking for these mutations, then you find — that's another targetable mutation. And they’re showing it in patients with biliary cancer. So it comes under the same theme or story.

DR LOVE: Right. What about the KEYNOTE 177 MSI high?

DR PHILIP: As you know, the original study was already presented. Here, what they were showing, they were looking at health-related quality of life. The analysis of 294 patients, half of them who received pembro, compared to chemotherapy, which was the standard of care treatment, there was an improvement in the health-related quality of life compared to standard of care. Obviously, these are patients who have MSI high tumors.

So, it's really important because at this point in time we are moving into using single-agent treatment in the frontline therapy of metastatic disease that have MSI high. And this just reinforces that you can even get maybe a better quality of life with it. So, it just reinforces what is now becoming more of a standard of care.

DR LOVE: What fraction of people with metastatic colorectal cancer, MSI high, roughly?

DR PHILIP: Five percent.

DR LOVE: Hmm. Okay.

What about this CheckMate 577, the adjuvant nivolumab study?

DR PHILIP: Yeah, that's an important one. So this study in esophageal mainly, and GE junction. So in esophageal cancer, unlike gastric cancer, and especially in squamous cell esophageal cancer, there is really no adjuvant treatment. So this will be the first time that you're developing an adjuvant treatment in patients who have esophageal squamous cell especially, as I said. And it doubled the disease-free survival.

I don’t think they had overall survival yet, but certainly very interesting because for the first time you have a treatment in the adjuvant setting in patients who underwent resection, but also, remember, those patients usually get the neoadjuvant chemoradiotherapy and then resection. And after that there’s nothing we do. And here, there is a treatment option now.

And if I want to think of how many patients will benefit from this, I would say it's going to be up to 10% of the whole population of people labeled as esophageal cancer. So if you take 100 patients with esophageal cancer, newly diagnosed, the capture is around 10%.

DR LOVE: That's a pretty significant step forward.

DR PHILIP: It is. It is an unmet need area. It's a truly unmet need situation.

DR LOVE: Also, kind of maybe gives a little bit of hope for other adjuvant studies that are cooking out there.

DR PHILIP: Possible. Yeah.

DR LOVE: Any that you think will be maturing soon? Colon, for example? Adjuvant colon?

DR PHILIP: No, colon is still running. No, it's not going to be — I don’t think anytime soon. No.

DR LOVE: Right.

DR PHILIP: But the colon is different — in patients who have — yeah, I mean it's different, MSI high.

DR LOVE: No, for sure. Yeah, MSI high. Right. How about the T-DXd paper there? That's different than the one that was presented at ASCO?

DR PHILIP: Yeah. So, one of the claims about the T-DXd is that the way the drug is — it can work even if you have a — when we talk about antiHER2/neu treatment, automatically you say overexpressers, all that stuff, right, IHC overexpressing and all that. But as you know, I mean these molecules are present in every cell, except that we’ve been treating patients who only have a high expression level. But this molecule, the T-DXd, is also believed that it has a good binding ability, even at low level of the HER2 expression. Do you understand that?

DR LOVE: Yes, absolutely. The same thing in breast.

DR PHILIP: So basically here, they're saying they have multiple cohorts in that study, you’re talking about the DESTINY-1, which is published in the New England Journal. And here, they’re focusing on the lower expressers and they’re seeing some response rate. It's not as, obviously as robust as you see in the other overexpressers, but there is some benefit. And there’s a DCR rate of 70+%. So there is some activity, but I would say that if you’re desperate it might be an option for a patient who doesn’t have anything else to do.

DR LOVE: Yeah, I didn’t see that it was HER2-low. That's really interesting. There’s not that much data in breast that I’ve seen on HER2-low yet. But I have heard about that.

What about CheckMate 649, nivolumab plus chemo.

DR PHILIP: So this trial looked into the combination, so it will include gastroesophageal, GE junction and gastric cancer and also esophageal. So, it will include all of it. And in this trial they showed that combining it with chemotherapy, the nivolumab again produced a benefit. And here you’re looking at hazard ratios in the region of 0.7 to just under 0.8 type or thing, or 0.8. So, certainly a benefit for the patients. And I think nivolumab will be leading the pack in terms of frontline treatment when combined with chemotherapy. So that's where the money is now.

In this trial, they also enriched the trial by putting their primary endpoint in patients who have CPS score of at least 5. So they did use a CPS score; whereas, in the initial trials that they had the ATTRACTION, which were later lines of treatment, they did not really base it on a biomarker. Here, they put the biomarker in, which is nice. So that means that there is an enrichment. And hazard ratio, PFS, 0.68.

DR LOVE: Is that enough for you to do it?

DR PHILIP: Yes.

DR LOVE: Hmm. Interesting. How about this other study with this nivo plus chemo in the ATTRACTION-4 study?

DR PHILIP: So, the ATTRACTION-4 is using GE junction and gastric, so there’s no esophageal. And again, the primary objective was progression-free survival that it made it, but it did not make it to this survival improvement. So, again, I think this study is positive, but it doesn’t show survival benefit. But in the presentation, it doesn’t show it.

In the presentation — this is important — 38% of the patients who progressed on the non-nivolumab arm and went on subsequent treatment, they did get immunotherapy. So a third of the patients did get immunotherapy in subsequent lines, which might have affected the survival.

In the previous trial that we talked about, the CheckMate 649, I think. Yeah. In that trial, the patients who went second-line treatment was only 8%. Here it's 38%. So that difference in second line or subsequent treatment with immunotherapy may explain why one of them had a survival benefit, one didn’t.

DR LOVE: That's really interesting.

DR PHILIP: From the global perspective, the second trial, the ATTRACTION-4, is an Asian trial. And the other one, CheckMate 649, is a global trial and only 25% of the patients were from Asia. So that's one of the things that I think will raise questions how is the approval going to be between the West and Asia? Because the concern for the Asian trial, ATTRACTION-4, is that they didn’t show a survival benefit. But then again, the primary endpoint PFS was met. So, I personally think that it probably will be approved, even in Asia.

DR LOVE: This concludes our program. Special thanks to Dr Philip, and thank you for listening. This is Dr Neil Love for Oncology Today.