Oncology Today with Dr Neil Love: Gastrointestinal Cancers Edition 2019 — Gastric Cancer (Audio Program)
Oncology Today with Dr Neil Love: Gastrointestinal Cancers Edition 2019 — Gastric Cancer
Jaffer A Ajani, MD Joseph Chao, MD 1.5 AMA PRA Category 1 Credits™
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KEYNOTE-181: Overall survival improvement with pembrolizumab versus chemotherapy as second-line therapy for patients with advanced esophageal or gastroesphageal junction (GEJ) cancer with a PD-L1 combined positive score (CPS) of 10 or higher DR LOVE: Welcome to a special 3-part audio program recorded during the January 2019 Gastrointestinal Cancers Symposium in San Francisco focusing on the selection and sequencing of systemic therapy for patients with advanced colorectal, gastric and hepatocellular cancers. This is medical oncologist Dr Neil Love. For this third issue focusing on the management of advanced gastric/gastroesophageal cancer, I met jointly with Dr Jaffer Ajani from the MD Anderson Cancer Center in Houston, Texas and Dr Joseph Chao from the City of Hope Comprehensive Cancer Center in Duarte, California. To begin Dr Chao commented on the potential clinical implications of the Phase III KEYNOTE-181 trial of pembrolizumab versus chemotherapy in second-line therapy for advanced esophageal cancer, which was presented at this meeting. DR CHAO: So a large Phase III study, KEYNOTE-181, definitely met at least 1 of its primary endpoints in terms of — they actually had 3 primary endpoints for their Phase III study comparing second-line pembrolizumab versus standard of care paclitaxel for esophageal, both squamous and adenocarcinomas, specifically in terms of the combined positive score PD-L1 testing. For those in which their score was at least 10 or above, they actually did show a significant survival benefit as well as progression-free survival benefit. So this is definitely clinically meaningful. I think many guidelines will be looking at this, and likely there’ll be regulatory approval shortly coming for this indication. DR LOVE: Jaffer, what was your take on these data? And also the issue that came up in terms of the histology, adeno versus squamous? DR AJANI: So I think we already had some hints that this is likely to be more beneficial for squamous histology. So there have been studies already published with nivo and pembro in squamous carcinoma of the esophagus showing higher response rates. Also, the PD-L1 positivity is a little bit higher, especially if you look at the CPS score and also the TPS score, which is just a scoring tumor for PD-L1 expression. So I think we have to wait for additional data, but it’s going to shake out, in my opinion, to be more beneficial for squamous histology than for adeno histology. Because for adenocarcinoma we already have some data showing that the PD-L1 positivity is lower than for adeno of the stomach, and squamous is higher. So squamous is high, adeno is low and then gastric is higher. So I think these data are more meaningful for squamous carcinoma, and there is another study, ATTRACTION-3, which is — we don’t know a lot of details, but that study is also comparing nivolumab to paclitaxel, and the press release says that the study is positive for survival. And they don’t even talk about CPS score there. So I think it may be that maybe in general that the checkpoint inhibitors will be beneficial for squamous histology — will show some benefit. And when you go up to CPS 10 and above, of course the benefit is going to increase. So I think this is where we want to go, because we know there are subsets in the patients that we see in the clinic. And we don’t recognize that. But this is going to give us some idea as to how to separate out the patients who are very likely to benefit and those who are not likely to benefit. DR LOVE: Joseph, can you talk a little bit about, assuming there’s regulatory approval or you could access treatment, what’s a situation where you might be thinking about using a checkpoint inhibitor in these kinds of patients? DR CHAO: Right, so I agree with Dr Ajani in terms of squamous histology, esophageal cancers, metastatic, patients went through first-line therapy, and unfortunately these patients invariably demonstrate progression. So for those in which we then subsequently do the PD-L1 testing by the combined positive score assay using the 22C3 Dako-approved agent for those with that score of at least 10 or above, then I think the data is pretty clear in terms of benefit for these patients over our historical chemotherapy. DR LOVE: Jaffer, can you envision a situation, maybe an elderly patient, where you might want to use a checkpoint inhibitor up front? DR AJANI: Yes. And, in fact, we are asking some of the patients like that, where you’re a little bit hesitant to give them combination therapy. And they are turning down chemotherapy because, as we all know, that at least the PD-L1 inhibitors are much better tolerated than chemotherapy, if you think about combination chemotherapy. So yes, I think we can envision that. Selection and sequencing of systemic therapy for metastatic gastroesophageal cancer in the age of immune checkpoint inhibitors DR LOVE: So I’m going to move on now and talk a little bit about the issue of sequencing of therapy, particularly getting beyond first-line therapy of metastatic gastroesophageal cancer and the options that come up in clinical practice and how you sort through them. Joseph, in your own mind, how do you think about the sequence of therapy and how it varies based on various clinical factors? DR CHAO: Sure. As I think with the current data that’s published, current guideline recommendations for initial diagnosis, we’ll start with gastroesophageal adenocarcinoma. Actually a lot of the Phase III data is really in that histology. With initial diagnosis, HER2 overexpression definitely plays a major factor in terms of whether or not to incorporate trastuzumab to standard front-line platinum and fluoropyrimidine therapy. Actually many of us involved in NCCN do believe the toxicity profile of FOLFOX is very favorable compared to high-dose cisplatin and 5-FU. Definitely move away from triplets that contain epirubicin, given some recent data in the last few years. But then for those patients who subsequently progressed on first-line therapy, paclitaxel/ramucirumab currently is the reference regimen based on the RAINBOW study, given survival benefit over just single-agent paclitaxel. But when we get into third line, it certainly — there seems to be more options emerging. Of course from KEYNOTE-059 with the accelerated approval of pembrolizumab in those in which the combined positive score of PD-L1 expression is at least 1 or above, we could use pembrolizumab single agent in that patient population. But then for those in which their PD-L1 is 0, essentially no evidence of expression, historically we’re still usually left with irinotecan therapy. But now there seems to be emergence with TAS-102, trifluridine/tipiracil, based on the Phase III TAGS study, so that definitely did show an overall survival benefit in patients who are in third-line therapy and beyond compared to placebo. They met their endpoints in terms of both progression-free and overall survival. They also had interesting analysis in terms of prevention of deterioration of performance status. These were good performance status patients who were enrolled on the study, ECOG of 0 and 1, so certainly it does present a challenge in which these patients are typically very ill. They may not have that performance status, but at least for those with still good performance status in which we may not have a good trial to offer them, certainly TAS-102 could be a consideration for these patients. DR LOVE: Anything you want to add to that? Or any differences in terms of how you approach the patient with MS-stable, HER2-negative metastatic disease? DR AJANI: No, I think the ranking that you outlined, I completely agree with that. So if HER2 is negative, then you just do a platinum compound and fluoropyrimidine, and preferred is FOLFOX. Then the second line is very solid, ram/paclitaxel. I think it will be hard to shake that, and there are a lot of strategies being thought around that, how to unseat ram/paclitaxel. So that is solid. In the third line, I agree that it would be preferred to go with pembro, at least in the US, because we have approval. Because if you think about TAS-102, I personally don’t think it’s all that very good drug, because it has almost no response. And in third line, although these are selected patients in the trial, but in the clinic most of these patients are highly symptomatic. And you really need relief of symptoms, and then you think about survival later on, even if you think about survival. At 12 months it’s only 7% improvement at 12 months in the experimental arm. But if you think about pembro, it is double. The 1-year survival rate is about 14% for PD-L1 positive patients compared to — the delta is 14%. And you get a tail with checkpoint inhibitors for those who are benefiting. This is irrespective of tumor type. You get all these tails of stability and responding patients that you’re not going to get with TAS-102. So I would put it towards the end, for selected patients who are not very, very symptomatic, maybe those who have very low-volume disease. So I think we have to be careful when we’re using that drug in the clinic. DR LOVE: I don’t — it sounds a little bit like the issue with colorectal cancer, that it’s used after everything. It doesn’t seem to help that much, but relatively tolerable. There are some data with regorafenib in gastric cancer. Is that an option? Would you ever even do that outside a trial setting? DR CHAO: So at this point, I would not. The data you speak of, it’s the INTEGRATE trial. It’s at least randomized Phase II data. There is an ongoing Phase III, which actually I’m personally not participating in, but certainly it would be of interest to see if that’s a positive study. It is compared against placebo. But I think it may, even with that study being positive, with the toxicity profile of regorafenib. Of course, in colorectal cancer there’s been strategies to look at alternative dosing. Really, to my knowledge, I don’t believe the Phase III study is looking at the alternative dosing, but certainly if there’s not a good clinical trial then, which I can offer a patient, they still have at a least fair performance status to tolerate such therapy, then possibly, at least after seeing the data, would I consider it. KEYNOTE-061: Results of a Phase III trial evaluating pembrolizumab versus paclitaxel for previously treated, advanced gastric or GEJ cancer DR LOVE: Focusing a little bit more on second-line therapy, Jaffer, can you comment on the KEYNOTE-61 study that was published in The Lancet — I think it was actually presented here at ASCO GI a year ago, pembrolizumab versus paclitaxel. What was seen in that study? And what you think it means. DR AJANI: So they made a really big mistake, and they had asked us to participate, and we said no. So first of all, taxanes are good drugs for gastroesophageal cancer. And they decided at that time, several years ago, to go against it. I think that was a big mistake. I told them that you should have designed the study like ATTRACTION-3, that goes with chemotherapy instead of going against chemotherapy. DR LOVE: So you wanted to see a combination of chemo and checkpoint, like lung cancer. DR AJANI: Yes. They would have won if they had combined pembro plus taxane versus taxane, instead of pembro against taxane. DR LOVE: Interesting. DR AJANI: The study was negative. But there were a couple of things there — DR LOVE: It was no difference. DR AJANI: Yes. There was no difference. So there was no survival advantage. But there was subgroup analysis of CPS, I think more than 10, that there was advantage. So that reminds us of KEYNOTE-181. Like, there is a subgroup of patients who benefit considerably. But if you want to capture the entire population, then the study should have been pembro plus taxane versus taxane. Durability of response to and ongoing evaluation of PD-1 inhibition in combination with ramucirumab for advanced gastroesophageal cancer DR LOVE: What about the issues of anti-angiogenics with checkpoint inhibitors? We’ve seen data, for example, in lung cancer looking at atezolizumab chemotherapy and checkpoint inhibitors. There’s a paper here, a Phase I/II study, looking at ramucirumab and nivolumab. Any thoughts about that strategy? I’ve been hearing about this idea of anti-angiogenics and checkpoint inhibitors in renal cell cancer. Of course, you see that with TKI axitinib and checkpoint inhibitor. What about in this situation? Any thoughts about that? DR CHAO: So yes. There’s both, actually some exploratory first-line cohorts that are utilizing that combination, as well as refractory setting. The response rates, I think, are still modest in some ways, certainly the durability of response. At least a proportion of patients with durability of responses does appear promising. Though I think it is challenging in terms of how to move forward with that. Certainly with the first-line data the hope was that potentially you could have a double biologic first-line treatment, chemotherapy, ramucirumab, PD-1 inhibitor. But with the RAINFALL study being negative in terms of trying to improve overall survival for front-line chemotherapy plus ramucirumab, then it doesn’t appear that would be an adequate space to introduce that strategy. So in terms of second-line therapy, while in many ways we’re actually waiting for PD-1 inhibitor data in the first line, both KEYNOTE-62 and, actually, for squamous cell histology esophageal cancers, 590 is actually an ongoing Phase III study. So I think we’ll have to see how that data shakes out, because if patients are having first-line PD-1 inhibitors, in terms of whether or not to continue immune checkpoint inhibitor, whether or not it’s with a VEGF inhibitor, then we’ll likely need new data sets to really explore that. Role of microsatellite instability (MSI) testing in gastric cancer DR LOVE: Jaffer, what about the issue of MSI in gastric cancer? How often do you see it in metastatic disease? And what do we know about the optimal strategy for those patients who are MSI high? DR AJANI: So data are very limited. If you look at the localized gastroesophageal cancer, for TCGA or the Korean data, the frequency is a little bit higher than metastatic. It varies from 15% to 20%. And this is also true in many other tumor types, that for localized disease there is higher MSI high — DR LOVE: Colon? DR AJANI: Yes. Colon. Uterus. But when you are in the metastatic setting, it’s very rare. It’s, like, 2% to 3%. And, in fact, I’ve got a huge practice of gastroesophageal — come across maybe 3 or 4 patients since we started doing this. But it’s a very, very good biomarker. Better than any biomarker for immunotherapy that we know. So if the MSI is high, then the likelihood of response, with the limited data that we have, is close to 50%. And then what happens is that the response duration is much longer than chemotherapy, and also overall survival is so much better than you will ever see with chemotherapy. DR LOVE: Do you think MSI testing should be standard in any patient with metastatic disease? DR AJANI: Yes. It is now recommended. It’s in the NCCN Guidelines. And since the approval of pembro in tumor-agnostic setting for MSI-high tumor, we are doing it. And, in fact, we had a discussion just a few days ago. There are certain groups of physicians with different tumor types. Because of very low frequency, they are not doing it routinely. But we probably should be doing it, because it consumes the tissue. It depends on how much tissue you have. Incidence of NTRK (neurotrophic tropomyosin receptor kinase) gene fusions in patients with MSI-high gastric cancer DR AJANI: So I want to bring up this NTRK fusion, and that was also approved tumor agnostic, very high response rate — DR LOVE: You see that with gastric? DR AJANI: Yes, we do see it occasionally with gastric. It’s only 1% in gastric population, but if the MSI is high, then it is, like, 36% or 38% fusion. So I think this is something good to understand. If you have MSI-high patient and they are responding to checkpoint inhibitor and then having progression or they are not responding to checkpoint inhibitor, which is, like, 50%, you should probably do NTRK fusion on them. DR LOVE: Wow. I’ve never heard of that. There’s a high level of NTRK in gastric? DR AJANI: MSI-high patients. DR LOVE: Oh, MSI high. So MSI anywhere? Or just gastric? DR AJANI: Anywhere. DR LOVE: Wow. I’ve never heard that. DR AJANI: Yes. So NTRK fusion is much higher when you have DNA damage repair deficiency. DR LOVE: Are there trials combining checkpoint inhibitors and NTRK inhibitors? DR AJANI: Not that I know, but I think it should be probably done. So in other words, every MSI-high patient should have NTRK testing done. DR LOVE: That is really fascinating. Second-line therapy options for patients with advanced gastric or GEJ cancer DR LOVE: Going back to this issue of second-line therapy, Joseph. In your own mind, you have a patient that is started on FOLFOX. Maybe they respond a little bit or they progress. As I’m sure a lot of patients, they see commercials on TV for checkpoint inhibitors. There’s a lot of awareness about checkpoint inhibitors. How do you go through with them the risks and benefits of, for example, pac/ram versus a checkpoint inhibitor? DR CHAO: So, actually, adding to the MSI data, in KEYNOTE-61 they did look at a small subset that were MSI high, and essentially that’s were we have a lot of the 50% response rate data. It does appear like it’s being maintained across lines of therapy. KEYNOTE-59 also showed that same data. So, actually, in the guidelines, in those patients who have microsatellite instability, you can consider pembrolizumab in the second-line setting. But outside of that, for microsatellite-stable disease, given the fact that KEYNOTE-61 didn’t meet its primary endpoint, at this point it’s not standard of care to consider checkpoint inhibitor, at least in second line. But certainly in terms of advising about toxicities with immune checkpoint inhibitors, I usually try to explain to patients that your immune system’s a bit too enthusiastic. Instead of only attacking tumor, it can affect normal organs, affecting intestines. I advise them about the diarrhea, risk of gastrointestinal toxicities, liver/hepatic dysfunction. So I tell them it’s not trivial if these toxicities are severe. But, thankfully, across the board, in terms of the safety signal that we’ve seen in pembrolizumab in GI cancers, it doesn’t appear to be that different than other tumor malignancies, at least less than 5% in terms of severe Grade 3 or 4 toxicities. DR LOVE: Again, getting back to this risk/benefit issue in the second-line setting, Jaffer. If a patient asks you, or you want to go through with the patient the potential for benefit, the likelihood they’re going to have a response or they’re going to benefit from treatment. Globally, how do you compare for them the option, outside of label, but the option of a checkpoint inhibitor versus pac/ram? DR AJANI: So I think for all comers in second-line setting with PD-L1 positive tumor, MS stable, the checkpoint inhibitors are not very good drugs. In second line or third line. Because 90% of your patients are going to progress pretty rapidly. So this is why I think we have to, again, focus on the heterogeneity and find better biomarkers to identify patients who are going to benefit, like MSI high. I would immediately jump on giving that patient, in second line, or even first line you can make an argument. But if the MS is stable, then I think ram/paclitaxel provides a high response rate, symptoms relief and a higher fraction of patients are likely to benefit. So I will save the checkpoint inhibitor for later on. Compared to, like we said, TAS-102, pembro is better, but pembro in general is not a very good drug. Neither is nivo, because a small fraction of patients are benefiting. DR LOVE: Joseph, what about the issue of ramucirumab alone without paclitaxel? There was a trial prior to the — that looked at that. For example, in a patient either with preexisting neuropathy or a lot of treatment-related neuropathy, is that an option you’d consider? Though in terms of prospective data, we’re actually still waiting for — there is a randomized Phase II that’s ongoing in Europe, the RAMIRIS study, that is looking at FOLFIRI versus paclitaxel. Hopefully that will give us some signal that possibly we can pair ramucirumab with, again, a non-neurotoxic chemotherapy regimen. Certainly, we have that data in terms of safety for colon cancer, quite a large data set, Phase III study in colon cancer, in which that regimen is both active and has an acceptable profile. So hopefully we then have an alternative to paclitaxel because of the neuropathy issues. Modulation of the gut microbiome to enhance response to anti-PD-1 immunotherapy; impact of antibiotic use on response to immune checkpoint inhibitors DR LOVE: Jaffer, I have to ask you, because I think I remember talking about this in the past. There’s a paper here — been lots of papers — there’s 1 here at ASCO GI on the impact of antibiotic use in response to checkpoint inhibitors that gets into the whole microbiome, which we could talk about for hours, probably. DR AJANI: Yes. DR LOVE: But just to cut to the chase, any thoughts about this issue of the microbiome and checkpoint inhibitors and this issue of antibiotics? DR AJANI: So I think this is a new but very hot area. And you remember the science paper from MD Anderson, where — may I explain that? DR LOVE: Sure. DR AJANI: So basically what they did was, they had more than 100 melanoma patients, and some had responded to checkpoint inhibitors and some did not. They took patients’ microbiome, colon microbiome and then profiled them, and then they found different signatures. And then they took that information to a mouse model, where mice — all the microbiome was ablated in mice, and they introduced human microbiome in mice. And if you changed the microbiome to the responding patient’s microbiome, the mice also responded. So in other words, there is a set of bacteria, if you have that in your gut, you’re going to respond to checkpoint inhibitor. That’s the idea. And of course the complexity of this is enormous, to understand how that happens. So I think there are now data, very interesting data, looking at microbiome and everything else, like hepatitis or colitis. So in other words, which toxicity you’re likely going to get, there’s a microbiome signature up here to correlate with the response. So this is a very new area, and it may be that instead of antibiotic we will be doing fecal transplant ahead of time in patients and then giving them immunotherapy — checkpoint inhibitor or whatever else you want to do, like cell therapy or whatnot. But I think this is very, very important, because the data in general with microbiome, not just cancer but in general, seems to be that there is a very high regulation. What bacteria you harvest in your entire body, not just the colon, but everywhere else, as related to your germline, and then all this interaction — what makes you and your disease and response to therapy and toxicity and allergy. All that seems to be likely a continuum. DR LOVE: Any comments about this paper that was presented here at ASCO GI — was actually multiple types of cancer, but looking at this issue, saying that there seems to be correlation between the use of antibiotics and, I guess, lack of benefit. DR AJANI: Yes. Lack of benefit, of course. So there have been some papers before this where they said, if your patient gets antibiotic just before they get checkpoint inhibitors, you’re reducing the effect of the checkpoint inhibitors. And this is just a correlative study, but we really need to have in-depth understanding of what is really happening. DR LOVE: Any follow-up comments on that? DR CHAO: Certainly I agree with that. The microbiome is a very major area of research, and, in fact, patients currently enrolled on trials with immune checkpoint inhibitors are actually getting stool samples collected now. Patients certainly give us a puzzling look in terms of asking for their poop, but — DR LOVE: So you’re doing that in your own center? DR CHAO: Yes. We are. DR LOVE: Wow. Interesting. DR CHAO: Both investigator initiated as well as the industry sponsored trials are, this, again, because its merge is such a major issue. But I think there’s still a lot of challenges in terms of timing of the stool collection. You can wake up in the morning, and in talking to other scientists who’ve done this work for quite a many number of years, that your microbiome could very, very much in the afternoon, after eating breakfast and lunch, versus what it was in the morning when you first wake up from fasting. One thing I do want to add in terms of, again, looking at responses to immune checkpoint inhibitors in the tumor genomics is, with MSI there is some emerging data that is very interesting in heterogeneity of microsatellite instability actually within the tumors itself. There’s actually data from a Korean Phase II study that actually also looked at EBV as being a very positive marker correlating with response to immune checkpoint inhibitors in gastric Stage IV cancer, in which different areas of the tumor — this is more in the cases that are sporadic in terms of causes of microsatellite instability — in which you may have loss of one of the mismatch repair enzymes in one region of the tumor but then subsequently still retention in other areas. And this Korean Phase II study actually had very nice data in terms of looking, with the subsequent PCR correlation with lack of microsatellite instability, in those regions in which they still have retention. And at least for this data set that those patients with that heterogeneity, they actually did not have a durable response to pembrolizumab. I’ve personally only seen it myself 1 time in terms of heterogeneity. The pathologist may comment on it if they at least have a large region of tumor to look at, possibly some regions that have staining, some regions that don’t have staining. I think we’ll need to collect that data more prospectively in order to see if that may be a mechanism of at least primary resistance or even acquired resistance. DR LOVE: That’s really interesting. Case (Dr Ajani): A 65-year-old man with MSI-high, moderately differentiated adenocarcinoma of the esophagus experiences an objective response with pembrolizumab DR LOVE: Why don’t we go through a few cases. And speaking of MSI, Jaffer, maybe you can talk about your 65-year-old man? DR AJANI: Okay. So this is a very interesting situation here. So the gentleman had a lower esophageal moderately differentiated tumor, metastatic. HER2 was negative. And also the PD-L1 was negative by CPS score. But as we discussed before, that we do the MSI testing, and we leave it up to our pathologists to select the method. And they are leaning on the 4 mismatch repair proteins by IHC, and I want to address that issue a little bit later on. But it turned out that he has 1 of the 4 proteins is not staining. So that means there’s a mutation there. So considered MSI high. And so we put him on pembro, and he’s responding very well right now. He’s got symptomatic relief. He’s got objective response. And hopefully it will go on for a long time. DR LOVE: And how long has he been on therapy at this point? DR AJANI: About 5 months. DR LOVE: Any tolerability issues? Any autoimmune problems? DR AJANI: Absolutely nothing. DR LOVE: Interesting. DR AJANI: So there are 2 things I want to mention. One is that you expect PD-L1 to be positive in MSI-high patients, because the immune system is more alerted, and tumors have the radar detector. They know the immune cell is around, like a T cell, and the way they know is because they can sense the interferon gamma. So T cell will elaborate interferon gamma, and tumor cells can sense that. So then they will express PD-L1. So at least from the current understanding, that’s the way it works. Like tumor is not going to express PD-L1 for nothing, because it costs energy, right? It’s not efficient. So it will only do it when there is a reason to do it. So in this particular case, PD-L1 is negative, which is kind of surprising. DR LOVE: I never thought about that. In general, are PD-L1 levels high in MSI-high patients? DR AJANI: Yes. Higher than in the MSS patients. DR LOVE: Hmm. Interesting. But in spite of that, he responded. DR AJANI: That’s right. Testing for common DNA damage-related genes and proteins as potential therapeutic targets for immune checkpoint blockade DR AJANI: And the second thing I want to mention is the testing. So there are 2 other proteins. One is ARID1A. It’s a tumor suppressor, and there is a mutation for loss of function of ARID1A. And what ARID1A does is, it’s an adaptor protein for one of the mismatch repair proteins to load onto the DNA. So you cannot really load onto DNA unless this adaptor is helping you. If this is mutated, 1 of the 4 proteins, I think it’s MSH6, which collaborates with ARID1A. So if you don’t have ARID1A, MSH6 can be perfectly normal. There’s nothing wrong with the genomic sequence, and there’s nothing wrong with the protein, but it cannot function properly because it’s not being helped by ARID1A. So if you just test for this, it can be perfect, but still you may have a high TMB. And this was reported by our group in Nature Medicine last year. The second one is the PALB2. PALB2 is another adaptor protein for BRCA1 and 2. So your BRCA1 and 2 can be perfectly normal, but if your PALB2, which is another tumor suppressor, has loss of function, you get high tumor burden. You get cancers because of that germline mutation of PALB2. You get breast cancer. You get pancreatic cancer. You get gastric cancer. DR LOVE: Ovary. DR AJANI: Ovarian cancer. DR LOVE: So are you saying that PALB2 tumors respond to checkpoint inhibitors? DR AJANI: Yes. DR LOVE: Really? DR AJANI: Yes. They are some very initial data. Because they have a high tumor burden also. So if you have loss of PALB2, it’s like having BRCA1 or 2 mutation. DR LOVE: Do you see response to checkpoint inhibitors with BRCA1 and 2 mutations? DR LOVE: More than non-BRCA1 or 2? DR AJANI: That’s right. There is some early data, because the TMB is higher. Of course, they’re more amenable to PARP inhibitors. But again, the whole idea is, you cannot repair your DNA. That means you’re going to have a lot of alterations. You add PARP inhibitor, you get even more alterations. And then checkpoint inhibitors are going to be more effective. The message I want to give is that we need to start looking at a lot of these adaptor proteins that may be abnormal, but you take these heavyweights like the mismatch repair protein or BRCA1 and 2, they may be completely normal, and yet there may be deficiency in DNA repair. DR LOVE: That’s fascinating. DR AJANI: But it depends on what method you use. People are really pushing for whole genome sequencing, which produces millions and millions of data points. You can’t really handle that in the clinic. So if you do immunohistochemistry, you’re going to miss a lot of other adaptor proteins. You do PCR, you’re just looking at the microsatellite instability, because PCR — so you have the mismatch repair proteins, and then you’ve got the damage. So PCR looks at the damage, and immunohistochemistry looks at the integrity of your repair machinery. So those are 2 different things. And how you assess this is an ongoing debate. So our pathologists, as I mentioned, they just want to look at the repair machinery rather than damage. The damage will be the microsatellite instability. And like Joseph mentioned and you also mentioned, there is immense heterogeneity in MSI-high patients. So, for example, the most frequent tumor is the uterine cancer, 30%, but the amount of damage is very low compared to colon cancer, is way up there. Then the gastric and small bowel and then others. Uterine will be here. So there is data to show that the degree of damage without checkpoint inhibitor has an effect on survival. And what is missing right now is whether the degree of damage, like MSI-high colon, has a higher response or not. This we don’t know for sure. DR LOVE: Any comments? I know when I’m going to talk to him it’s going to be like we’re going to leave the world for a while and come back, but anyhow. DR CHAO: No, it’s all great data. I mean, certainly there is that proportion of metastatic gastric cancers that have defects in the DNA repair machinery. I’m certainly always looking for those, when at least doing targeted sequencing, panel sequencing for my patients. I guess I’ll add there are ongoing trials looking at PARP inhibitors with PD-1 inhibitors. At least there’s still data waiting on safety, but certainly I think expansion cohorts looking at gastric cancers or other cancers with both paired DNA repair defects and possibly augmenting immune checkpoint inhibitors would be of major interest as a future direction. Case (Dr Chao): A 63-year-old man with poorly to moderately differentiated gastric adenocarcinoma receives third-line ipilimumab/nivolumab on a clinical trial DR LOVE: So let’s move back, though, to the more common MS-stable situation. And Joseph, maybe you can get into your 63-year-old man. What happened there with him? DR CHAO: Sure. So this is a 63-year-old gentleman in January 2016, so preceding a lot of the readouts for the current indications in checkpoint inhibitors. He had epigastric pain, GI bleeding symptoms. Subsequent endoscopy did show a large, fungating mass in the gastric body, which confirmed moderate to poorly differentiated adenocarcinoma, HER2 nonoverexpressing. Immunohistochemistry was only 1+ by scoring criteria. Unfortunately, he had metastatic disease at presentation, peritoneal metastases. Cytology confirmed malignant ascites. Went through standard of care therapy, first-line FOLFOX. DR LOVE: What was his status before, when you started the FOLFOX? Was he symptomatic? DR CHAO: Quite symptomatic in terms of his ascites. Actually, it was our surgeon who initially saw the patient, and actually because of how often he needed therapeutic paracenteses, he actually had a catheter placed in order to have the ascites removed at home. And thankfully he actually responded quite well to FOLFOX. Initially, the ascites dried up. He actually was able to undergo removal of the catheter. But, unfortunately, with this patient, actually, even before we would have scans was demonstrating progression. Usually it’s recurrence of ascites, more bloating symptoms, which we knew that he subsequently needed switching therapy. And subsequently he did have to go onto second-line treatment, in January 2017. So a year at this point, and we utilized paclitaxel/ramucirumab as standard of care second-line therapy. But then, typical in many ways in terms of median progression-free survival, where time to progression with second-line therapy, he progressed in June of 2017, so — DR LOVE: Did he actually respond to the paclitaxel/ramucirumab? DR CHAO: Actually, he did, so again, yes. The ascites went away again, and certainly there was a lot of, at least, hypotheses, about VEGF inhibitors allowing for a decrease in vascular leakage. DR LOVE: That’s interesting. You hear about that with bev, but I guess ramucirumab as well, aflibercept — I didn’t even think about that. DR CHAO: Yes. Yes, certainly many of us consider for that strategy. DR LOVE: Interesting. Any tolerability impact with the paclitaxel/ramucirumab? DR CHAO: No, thankfully. Neuropathy was minimal. We monitored the hypertension and proteinuria fairly regularly. Did not really progress beyond Grade 1 at any point, in terms of those toxicities. And, I mean, at least for myself, when I utilize first-line platinum-containing therapy, I’m actually pretty proactive. After 4 months of treatment, patients who have response, actually dropping out the platinum, even though there’s not as much data with fluoropyrimidine in gastric as opposed to colon cancer. I think many of us utilize that strategy in the academic setting and find it to be effective. And also maintain quality of life and then subsequently allow for us to still utilize agents that have neurotoxicity in later lines of therapy. Clinical experience with and management of immune checkpoint inhibitor-associated gastrointestinal and dermatologic complications DR LOVE: So what happened next? DR CHAO: Yes. So subsequently he was — this is now May/June of 2017. We’re still a bit a ways away in terms of — actually, this is still prior to the KEYNOTE-59 data being presented. It was, like, later that month. But, actually, we did have a clinical trial open utilizing immunotherapy combinations, and he actually was started on nivolumab and ipilimumab, so dual PD-1 and CTLA-4 inhibitor therapy. Actually initially did well with it. So with this trial, it actually had the same dosing as CheckMate 032 in terms of relatively lower-dose nivolumab, higher-dose ipilimumab, given every 3 weeks for 4 infusions before going on to single-agent nivolumab. And actually same as with first-line therapy and second-line therapy, his ascites recurred when he went on the trial. We actually had to put in another abdominal PleurXTM catheter to allow for drainage, but then subsequently his ascites went away again, so — and actually he also at that time developed a palpable abdominal mass, and actually it was impressive that the abdominal wall mass actually also responded to dual immune checkpoint therapy. DR LOVE: Abdominal wall mass. How often do you see that? Was that related to an invasive procedure or something? A peritoneal thing? DR CHAO: Yes. DR LOVE: Really? DR CHAO: Yes. We unfortunately can see seeding of the abdominal wall, both from diagnostic procedures, surgical interventions and in spite of our best intentions in terms of relieving ascites, I think most likely with removal of the catheter — actually, he had the catheter removed in earlier lines of treatment because of how well he responded. I think most likely there was seeding of the abdominal wall where the catheter was previously placed. DR LOVE: Just curious, and Jaffer, have you seen that? Seeding from biopsies or catheters? DR AJANI: All the time. DR LOVE: Really? All the time? Huh! DR AJANI: Especially if there is known peritoneal disease. DR LOVE: Oh, more with peritoneal disease. DR AJANI: Yes. So that will track. But spontaneously, it’s rare. DR LOVE: How about from biopsies or surgical procedures? DR AJANI: Only if they have peritoneal disease. Yes. DR LOVE: Interesting. So is the idea that it’s a combination of the peritoneal disease but also the catheter? That’s where it’s happening, where the catheter is? DR AJANI: That’s right. DR LOVE: Wow. Interesting. DR AJANI: Basically tracking. DR LOVE: So he actually has a response then in this abdominal wall met. DR CHAO: Yes. DR LOVE: What happened next? DR CHAO: Yes. So then we were very encouraged with the response. But, unfortunately, it wasn’t a GI toxicity, which was really my main concern being on dual immune checkpoint therapy. He actually developed a skin rash. Initially it was very limited, just some erythema, but very pruritic. And we advised him to start topical steroids, nonsystemic steroids as well as oral hydroxyzine to manage the pruritus symptoms. But, unfortunately, the skin rash continued to progress. It actually involved a greater amount of his body surface area. Actually really became hyperpigmented, almost reminded me of my fellowship days seeing GVHD. It was very thickened. DR LOVE: Wow. DR CHAO: So, unfortunately, it was still considered Grade 2, but it definitely interfered with his quality of life significantly. And, actually, we followed the protocol guidelines in terms of starting systemic high-dose steroids. At that point, we essentially dosed him at 1 mg/kg of prednisone. And, thankfully, he actually started responding to the steroids. The skin rash eventually went from Grade 2 to Grade 1 over about a 2-week period, and then we actually were hoping to get him back on immune checkpoint inhibitor therapy on a protocol. So then subsequently started tapering down the steroids. And then once he hit that level of 5 mg per day or less of prednisone, we were able to reinitiate the subsequently fourth dose. We actually had to delay the fourth dose of nivolumab and ipilimumab in order to allow for relief of the autoimmune toxicity. But, unfortunately, he did eventually develop progression despite resuming immune checkpoint dual therapy. DR LOVE: So I’m curious about the issue of dermatologic toxicity, Jaffer. In other cancers, when we talk about checkpoint inhibitors people always are focusing on pneumonitis, colitis, life-threatening issues. But when you really talk to docs in practice, because it seems like there are a lot of people with dermatologic problems. DR AJANI: Yes. I think it’s very common. There are two. The most common one is the thyroid. And the second one is skin. More often than internal organs. So I had a patient who had Stevens-Johnson — DR LOVE: Wow. DR AJANI: — and he survived that. Fortunately, he survived. But he was on the combination — DR CHAO: Doublet as well. DR AJANI: — with high ipi dose 3 mg and regular-dose nivo. DR LOVE: Just out of curiosity, did he respond? And do you think there’s a correlation between autoimmune toxicity and response? DR AJANI: So this is something I don’t know for sure. He responded, but in general whether those who have some sort of toxicity, immune-mediate toxicity, and whether their survival is better, whether they have a higher response rate, is not clear. I think we should be able to get that kind of data very soon. Case (Dr Ajani): A 58-year-old man with HER2-positive metastatic gastroesophageal adenocarcinoma receives ramucirumab/paclitaxel after experiencing disease progression on FOLFOX/trastuzumab DR LOVE: So let’s move on and we’ll finish out actually talking about HER2-positive disease. And Jaffer, you have this patient, if you could maybe talk a little bit about what happened? DR AJANI: So he’s in his late fifties, and he presented with widely metastatic, PET-avid disease. DR LOVE: Where was the primary? DR AJANI: Primary was at the GE junction. But there are two points I wanted to make. I think one of them was your point, but what happened was, he came from another state to us and already had HER2 testing done. But we couldn’t get the results. We just couldn’t get ahold of the doctor, and the office didn’t have the results. So we did our own. And it came back 3+. Then once we got that, the doctor calls me, and he said, I already did it. It was negative. So this is a point I want to make, is that the HER2 expression in gastric cancer compared to breast cancer is quite different. Breast usually has more diffuse. So if you’ve got tissue, small breast tissue, if you take a sample here or a sample there, you’re more likely to find HER2 positivity if it’s a HER2-positive tumor. In gastric cancer, if you take a sample here it can be positive, sample here it can be negative. DR LOVE: So this was a biopsy of the primary? DR AJANI: Yes. Both of them were primary. DR LOVE: But they were done at different times, or you got the tissue, the same tissue they looked at? DR AJANI: No. They took their sample, and we did another biopsy. DR LOVE: So you did another biopsy, and yours was positive and the other — and do you think the other one was a false-negative, or you think it really was negative, it was a heterogeneity thing? DR AJANI: It was probably negative. It was just heterogeneity. DR LOVE: Wow. DR AJANI: So that issue is totally unresolved with the ASCO and CAP Guidelines. It was hotly debated whether we should do multiple biopsies or not. And if you do multiple biopsies, do you want to test all of them? And then the pathologists were resisting, saying, “We’re not going to stain 6 slides from 6 samples and report to you,” and there can be confusion and extra work. So that brings us into liquid biopsy area also. So that’s one point. So he had a dramatic response to FOLFOX plus trastuzumab that lasted for almost a year, and then he had progression. So we started on ram/paclitaxel, and he had another dramatic response. DR LOVE: Objective response? DR AJANI: Objective response. Trastuzumab beyond progression for patients with HER2-positive advanced gastric/GEJ cancer DR LOVE: Can you just focus a little bit on when he did progress on the first-line therapy how you thought through options? Because one of the other options that would — and we asked this as a poll question. This is a classic case that we ask all the time. A lot of people want to keep the trastuzumab going, change the chemotherapy rather than giving pac/ram. You gave the patient pac/ram, and the patient did really well. But what about that other option? Keeping the trastuzumab going? Actually, there was a paper here at ASCO GI looking at that. It looks like they didn’t find any benefit. DR AJANI: There is no benefit. So we actually published before on maintaining trastuzumab, not beyond progression but when the patients don’t have progression. They have a response. They have stability. I have a patient who is on for 14 years right now, on trastuzumab. This is before the ToGA trial that we were doing this. So they have several patients, including one who was on trastuzumab for almost 9 years. So that’s a different scenario. But if you have progression, trastuzumab does not work. And if you look at the T-DM1 trial where patients had first-line trastuzumab with chemotherapy, HER2-positive tumor, then they were retested, HER2-positive tumor and were randomized to T-DM1 versus taxane, and that was negative. And there were a bunch of other trials that are negative like that. So the other thing I want to mention, this is a phenomenon that we don’t understand, is that the tumors continue to express HER2 protein, even if you give trastuzumab and tumor is clearly resistant. There is clear progression. Then you biopsy that, and it is highly expressing HER2 protein. So I don’t understand that, but this is also in breast literature. And we will probably, hopefully, be able to discuss some of the new HER2-targeted drugs. Again, this is in patients who are heavily treated, especially breast population, heavily, heavily treated with pertuzumab, T-DM1, trastuzumab, still got HER2-positive tumor. Then they get this new antibody, and they have a dramatic response. So why is this happening is totally unclear. DR LOVE: What about, Joseph, this issue of second-line therapy? Again, we ask this all the time in our meetings. Patient responds to FOLFOX/trastuzumab, then comes to the second line, again looking at this issue of trastuzumab continuing versus paclitaxel/ram. Do you usually do what was done in this patient and go with a paclitaxel/ram? And what about if the patient had, maybe not 9 years but a longer response, let’s say 2 years? DR CHAO: That’s a great question. I mean, these are all — we actually are getting more emerging data to try and address this. So in terms of second-line trastuzumab, yes, there’s retrospective data that appears like it’s beneficial. So because of the breast cancer data, certainly there’s been a lot of application of that strategy in metastatic gastric cancer. Though getting to this issue in terms of the heterogeneity of HER2 overexpression, I think there is that big difference between breast and gastroesophageal cancer. So actually it was ASCO last year in which there was — actually, I was very familiar with the abstract, because I led the poster discussion for it. Finally, there was a Japanese randomized Phase II study that actually prospectively studied, looking at, for patients who had initial platinum, fluoropyrimidine, trastuzumab, then going on to — they were actually randomized to paclitaxel with continuation of trastuzumab versus just paclitaxel alone. So really prospectively testing that strategy and in many ways trying to replicate the randomized breast cancer data. It was only a 90-patient trial, but at least in terms of our statistics looking at progression-free survival endpoint, it was adequate. And, actually, what’s funny, not often do I look in depth at the breast cancer literature, but actually that turned out to be about the same number of patients that showed that trastuzumab beyond progression was effective in breast cancer. So in this study, you actually don’t see any benefit with continuing trastuzumab beyond progression. But really what’s most striking is that they were able to sample, unfortunately only a small percentage, about 16 of their 90 patients. They actually, of course, had confirmation they were HER2 overexpressing at initial diagnosis, so they went on to first-line trastuzumab. But then before they went on to this second-line study, they had rebiopsies for these 16 patients. And actually it was quite remarkable. About two thirds of those patients had loss of HER2. DR LOVE: Wow. Interesting. DR CHAO: So you do have cases in which there’s loss of HER2, certainly, but you also have cases in which there’s still retention of HER2, as Dr Ajani has mentioned. But then, going back to Phase II studies being done in Korea, this was actually a Phase II trial led by Dr Jun Haeng Lee in which they actually — getting into circulating tumor DNA potentially being a promising way to track both spatial and temporal heterogeneity. You actually do see, for those cases in which there is retention of HER2 overexpression, there may be other codrivers that are subsequently enriched, such as METZ or FGFR2 or cyclin E1. So this, certainly, we’re now recognizing more and more that there’s quite a variability in terms of how resistance develops. There’s both loss of HER2 expression, which I would definitely argue that there’s not much benefit in giving the HER2-targeted agent in that setting. But then at least for those subset of patients in which there is still retention of HER2, then we can potentially explore still using HER2-directed strategies. But then we need to overcome the subsequent codriver mutations that are arising. So at this point I would not recommend utilizing trastuzumab beyond progression outside of a clinical trial. But, as Dr Ajani mentioned, there are new HER2-directed agents which appear promising, which I think we should put those patients on those studies to really then continue to look if HER2-targeted strategies can be effective. DR LOVE: Jaffer, another thing, and we saw this at the meeting we had here. When you present a patient who’s progressing on trastuzumab and chemotherapy, what you see a fraction of people talking about is pac/ram and trastuzumab. Any thoughts about that? DR AJANI: So that is, again, trastuzumab beyond progression. So right now, I think the — at least the upper GI community believes that once the patient has progression, HER2-positive patient has progression, then they are mixed with the rest of them. You don’t focus on HER2 anymore, because there’s really no good data to support HER2-targeted therapy, except a couple of molecules out there that are, like, emerging from Phase I and expansion cohort trials, which they are really very, very promising other molecules. So, in other words, I wouldn’t continue trastuzumab. Case (Dr Chao): A 74-year-old man with previously treated HER2-positive metastatic GEJ adenocarcinoma receives high-dose ramucirumab and paclitaxel on a clinical trial DR LOVE: So let’s hear about your 74-year-old man, Joseph. DR CHAO: Yes. So this is a 74-year-old gentleman in April of 2015. Really, his only presenting, I guess, abnormal finding was liver function testing being abnormal. His primary care physician subsequently was very proactive in terms of doing further investigation. Actually, he had a CT scan, which, unfortunately, demonstrated multiple liver lesions, quite enlarged. The largest was about 8 centimeters in the left lobe of the liver. But he also had some gastrohepatic enlarged lymph nodes as well. So an EGD was performed, on which actually there were findings of Barrett’s esophagus starting pretty high up in the esophagus at 24 centimeters from the incisors. But then further down it was a GE junction tumor. Actually a Siewert I, being fairly high up in the GE junction, from 34 to 39 centimeters. The biopsy did show adenocarcinoma. He actually was found to be HER2 overexpressing. The IHC scoring was 3+, so pretty strong signal for the HER2 biomarker being present. Started him on first line, at least my typical first-line treatment, again being FOLFOX, but then also trastuzumab. He actually was then on maintenance therapy with trastuzumab. Actually, he did very well with maintenance therapy, quite a prolonged period, from about 8 months, November through July of 2016. But then at that point, he subsequently had progression with regrowth of liver lesions. Previously had a very good response. He had normalization of his liver function testing. Dosing, efficacy and side effects of ramucirumab DR LOVE: What happened next? DR CHAO: Yes. So we of course talked about standard of care paclitaxel/ramucirumab as second-line therapy. Again, I usually do not utilize trastuzumab beyond progression. But we actually had a clinical trial that was actually examining different doses of ramucirumab, essentially high-dose ramucirumab versus standard-dosing ramucirumab. This was open label, so actually he went onto the high-dose ramucirumab arm with paclitaxel. Thankfully, for the most part tolerated therapy. He did have some neutropenia, which we already know from the RAINBOW trial that is not an uncommon toxicity with the taxane plus VEGF inhibitory combination. So with some dose delays. But then what was really interesting, too, is, actually, he developed some hypertension, so definitely VEGF-mediated toxicity. But then he was really complaining about a lot of scalp bleeding, a lot of scalp symptoms. And I was really puzzled by that. Not, I mean, it’s not — maybe the taxane leading to alopecia has some issues. But then really when I looked at his scalp, he actually had a small hemangioma that apparently was bleeding at times from, I would only presume, from the VEGF inhibitor therapy leading to abnormal vascularization. So, actually, usually with dose delays, thankfully that symptom did not progress any further. I’m definitely more mindful of these kinds of symptoms now for patients on VEGF inhibitors. DR LOVE: That’s really interesting. Have you ever seen that? DR AJANI: Yes. DR LOVE: You’ve seen everything. DR AJANI: We just cauterize them. DR LOVE: You cauterize — DR AJANI: If it’s safe. Like, a limited area. DR LOVE: Do you see that with bev and other anti-angiogenics? Or just ramucirumab? DR AJANI: Ramucirumab is the one that comes to mind. DR LOVE: Huh. So these are hemangiomas? That somehow the ramucirumab exacerbates? DR AJANI: Yes. Something triggers the new anti-angiogenesis — DR LOVE: Wow. That is interesting. DR AJANI: — and then ramucirumab will start or excite bleeding in there. DR LOVE: So I actually have never heard about this idea of changing the ramucirumab dose. At this point, what’s known about it? DR CHAO: So yes, at least the — actually, in many ways the prompting for this trial and then, actually, for the first-line RAINFALL trial was, at least from RAINBOW, and I believe REGARD as well, there was a post hoc analysis. This, essentially, I guess drug-level response relationship. Of course, with both RAINBOW and REGARD, patients all had the same dose of ramucirumab. But what’s interesting, there appeared to be these quartiles of patients, those in which I guess they process the antibody much more slowly, had higher ramucirumab levels. They actually had better survival versus those in which, for some reason or other, because of pharmacogenomics, processed the ramucirumab to lower levels. So actually for RAINFALL, there was a pushup in the dose, so day 1, 8 dosing as opposed to day 1, 15, every 28 days that was utilized in RAINBOW. But despite that strategy to try and increase the dose of ramucirumab, there was a progression-free survival benefit, but unfortunately the overall survival benefit still didn’t pan out in first line. DR LOVE: Really interesting. First-line pembrolizumab, trastuzumab and chemotherapy for HER2-positive metastatic esophagogastric adenocarcinoma DR LOVE: So just a couple final closing questions I have. Again, in terms of looking at this meeting, Jaffer, anything else that’s being presented or you’ve heard about that has you excited? DR AJANI: No, not really. DR LOVE: Joseph, anything that you’ve seen? Anything else at this meeting you want to comment on? DR CHAO: I know it’s, yes, this is only Phase II data at this point, but another major oral presentation was Yelena Janjigian’s data set in terms of combination chemotherapy with trastuzumab and pembrolizumab in the front-line setting, to in many ways try and augment the ADCC activity of trastuzumab. So, of course, Phase II, so we still have to take caution in terms of not necessarily considering that practice changing, but it is certainly very compelling in terms of the proportion of patients who had responses, the depth of responses and at least in terms of their survival outcomes with this early look, the median survival wasn’t reached yet. But at least the signal was definitely strong enough that there is a current Phase III that is ongoing, the KEYNOTE-811 trial that’s actually randomizing patients to addition of pembrolizumab to front-line chemotherapy and trastuzumab, again, in HER2-overexpressing patients. So hopefully, maybe even for low PD-L1 expression in HER2 there may be augmenting of immuno-oncology approaches with this strategy. Importance of appropriate therapy selection for patients with gastroesophageal cancer DR LOVE: Final question to both of you. First, Jaffer, any myths or misperceptions about the management of gastroesophageal cancer? You see second opinions of people coming in. We talked about MSI testing. But beyond that, anything that you see globally in gastroesophageal cancer, people doing in practice that maybe is not optimal? DR AJANI: A lot. Unfortunately, like we mentioned earlier, that the community oncologists are overwhelmed. I have fellows in practice who are saying they cannot even handle lung literature right now. There are so many drugs, so many biomarkers and then the next patient is breast cancer, another one is colon cancer. So when I see their patient with gastric cancer that already has received 1 line, it is often something that is not recommended. DR LOVE: Like what? DR AJANI: Like, they will use a taxane in the front line, or they use carbo/paclitaxel in the front line. Even the penetration of paclitaxel/ramucirumab is close to 30%. You won’t believe it, because the combination has been approved for several years now. And the private practitioners just cannot keep up with the wealth of data that’s out there. DR LOVE: Any comments, again, on specific things that you see people doing that maybe could be done better? DR CHAO: No, I would agree that of course FLOT generated a lot of interest for perioperative treatment, but I think both Dr Ajani and I agree that it is still for select fit patients because of the toxicity profile. But then I have noticed a lot more incorporation of FLOT in the metastatic setting as well, getting again back to this issue of front-line with triplet, with a taxane. DR LOVE: FLOT in the first-line metastatic setting? Has that been looked at in research? DR CHAO: Phase II data. DR AJANI: Phase II data. But it’s not sufficient to make it a standard of care. DR LOVE: Hmm. Interesting. DR AJANI: But people are just looking at the FLOT in the adjuvant/neoadjuvant data, and then they’re using it for metastatic patients that they were not doing before. Now they are doing it. DR LOVE: Wow. Any other observations? DR CHAO: So I think there’s — actually, Dr Ajani has done a lot of this research in terms of getting into earlier-stage setting. Of course, there are trials incorporating immune checkpoint inhibitors in the earlier-stage setting, both in Asia with the ATTRACTION-5 study and, actually, in the US, KEYNOTE-585 is actually looking at perioperative therapy, adding pembrolizumab. But in terms of molecular classification, hopefully we can finally look at molecular classification as distinguishing prognosis for these patients. There actually is at least post hoc analyses, so hypotheses generating that MSI actually could be a favorable prognostic factor in early-stage gastric cancer, as we already know from Stage II colon cancer. So, possibly, can we consider not doing chemotherapy for these patients? Still a research question, which I think we need more data, but certainly very compelling, in which we are changing usually what’s considered a very negative outlook for these patients. DR LOVE: Fascinating. Final thoughts? DR AJANI: So along the same line, I think the whole panel of DDR-deficient machinery, I think, in addition to MSI high and BRCA, we need to look at all these other genes that are, like, 27 genes, at least 27. But there are probably 900 of them. So we need to really select out patients who are likely to benefit with a PARP inhibition, PD-L1 inhibition or PD-1 or immunotherapy of some sort, segregating the subgroups that are likely to benefit. DR LOVE: This concludes our program. Special thanks to our faculty and thank you for listening. This is Dr Neil Love. |