Welcome to The GI Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).
This exclusive discussion features leading experts Tobias Arkenau, Deborah Mukherji, Kai-Keen Shiu, Lizzy Smyth, Nataliya Uboha and Susanna Ulahannan, who offer their perspectives on some of the key data and highlights from the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting.
In upper GI, the panel consider the practice-changing CheckMate 648 in the first-line setting for esophageal cancer and RATIONALE 302 in the second-line, as well as KEYNOTE-811 and MAHOGANY in gastric cancer. In colorectal cancer, they examine personalized first-line studies including DEEPER and BEACON, and maintainence trials including PanaMa and FOCUS4. They also consider Nal-Iri in biliary tract and pancreatic cancers, as well as exciting emerging therapies such as trastuzumab deruxtecan in DESTINY-CRC01.
“[On CheckMate 648], the readout was really amazing. So patients who were treated with chemotherapy had a survival of about nine months, which is what we expect. And we added nivolumab, we improved the response rate, the progression-free survival and the overall survival, overall survival being 15 months, which was really fantastic. And so, this is a practice-changing trial for those patients.”
– Lizzy Smyth
“So I think in terms of the global oncology view, those translational studies and knowing about the biomarkers and who really will benefit from either immunotherapy combinations or immunotherapy upfront is really where, academically, we should be trying to put more of our energy, if that’s possible.”
– Deborah Mukherji
“[On KEYNOTE-811], I share some of your sentiment that we’ve had some surprising approvals recently, but I think out of all of them, this was probably warranted. It was hard to ignore those waterfall plots, their response rate of over 70% with additional pembrolizumab. And also now coming out for two Phase 2 trials that showed similar responses, I think it’s difficult to ignore. And these patients have a lot of needs and this is a huge unmet need. And so, I think I am certainly going to start using immunotherapy in first-line setting in my patients with HER2 positive tumors based on these results.”
– Nataliya Uboha
mCRC in the first-line setting
“…the DEEPER study, a randomized Phase 2 study from Japan. And that was looking at the question of using triplet therapy upfront. So FOLFOXIRI, plus cetuximab or bevacizumab in patients with RAS wild-type colorectal cancer in the first line… And this trial chose an interesting end point of depth of response. And they were looking and the trial was actually positive. So the arm randomized to FOLFOXIRI plus cetuximab had a deeper response on average, but actually there was no difference in other markers such as overall response rate or resection rate, and no difference in the preliminary data for PFS and overall survival.”
– Deborah Mukherji
mCRC maintenance therapy: when less is more
“[On FOCUS 4], I don’t know if it’s necessarily practice changing, but what’s the flip side was CAIRO3 kind of said, in the responding patients, you should push maintenance, actually both in PanaMa and in FOCUS4-N, it says actually, you shouldn’t. And I liked this because it means the responding patients should have a break, a proper break. As in, if you’re clever about this, you don’t even need to stratify to ctDNA, or anything like that, you just say, look, these responding patients are probably going to do well. You can give them a six, eight, 12-week break. And the ones who need it are the ones that only achieve stabilization.”
– Kai-Keen Shiu
Biliary tract & pancreatic cancers
“In this study, they actually compared 5FU alone to 5FU plus Nal-IRI. Similarly to this study, NAPOLEON study, that was done in second-line pancreatic cancer. And it was a positive study, a significant improvement in OS, significant improvement in PFS. PFS was a primary endpoint. Of course, they can’t compare study to study, but numerically it looked better than FOLFOX. And I think for me, looking at their response rate, looking at OS, looking at the fact that would be a changing mechanistically one chemo agent, platinum agent, to a non-platinum agent, makes me more excited about this regimen as a possibility for my patients in second line”
– Nataliya Uboha
“I was very excited about the DESTINY-CRC01…I thought it was interesting that they did a three arm study looking at HER3-positive, or two-positive with FISH, ISH-positive versus two positive and one positive. Just thinking that this is the antibiotic drug conjugate, we just leave the drug to the tumor and it’s more the chemo and not a targeted pathway. But there was no responses in two plus or one plus, but all the data was in three plus.”
– Susanna Ulahannan
SECTION 1: Esophageal Squamous Cell Carcinoma
Tobias Arkenau: Hi, it’s Toby Arkenau here. I’m the Medical Director for Sarah Cannon Research Institute in London. I’m a GI oncologist. And I’m really excited to share with you, and a team of five colleagues around the world, the latest updates on GI cancers from ASCO 2021. And first of all, I want to say thank you to VJ Oncology to make this happening.
And so without any further ado, let me introduce you to Dr. Lizzy Smyth. Lizzy Smyth is Associate Professor at the University of Cambridge Addenbrooke’s Hospital in the UK, upper GI lead around the world, heavily involved in EORTC and ESMO. Next, very welcome to Deborah Mukherji and Deborah is also GI oncologist, Associate Professor at the American University in Beirut, and also heavily involved in GI and GU research, and works with ESMO and collaborates around the world with various different GI oncologists. Nataliya Uboha at Wisconsin Medicine Center, an Associate Professor there, leads the early Phase 1 program in GI cancers, and was this year’s discussant of the poster discussions at ASCO and will share her insight in some of the updates in GI cancer. And Susanna Ulahannan leads the Phase 1 center at the University of Oklahoma, and also GI oncologist. Worked in many early and late-stage clinical trials. Kai-Keen is a colleague of mine in London, oncologist at University College London and HCA.
So, let me start with probably the most exciting bits, really practice changing with Lizzy. Upper GI cancers, squamous cell esophagus, there have been updates and new entry of immunotherapies. Two relevant studies, KEYNOTE-648, and the Japanese study, ESCORT-1. How do you put them into the context of our current practice? How do you see these two studies practice changing, or do you see them practice changing?
Lizzy Smyth: Thanks for the question, Toby. First of all, I need to own up to not being an Associate Professor in Cambridge, or I’ll get in trouble at work, but thank you. I would like to be possibly in a few years. So squamous cell cancer of the esophagus is a really important global problem. Although we get a lot of adenocarcinoma patients in the UK and The States, globally by far, squamous is the much more common. And for many years, this was really an orphan disease, no drug development, so it’s fantastic to see these trials emerging with efficacy of immune checkpoint blockade for these patients and also changing the practice of care and helping these patients to live longer.
So, there were two trials for squamous cancers. The first that you mentioned was CheckMate 648. This was a global trial in which patients with previously untreated squamous esophageal cancer, which is advanced and incurable, were randomized to either standard of care chemotherapy, standard of care chemotherapy plus PD-1 antibody nivolumab, or a third arm with no chemotherapy and doublet immunotherapy. So anti CTLA-4 antibody, ipilimumab plus nivolumab. So, the first readout was for patients treated with chemotherapy plus nivolumab. And it’s interesting that the primary endpoint was in patients who were PD-L1 positive using a tumor marker for PD-L1, which was a TPS score signal. Over the past couple of years we’ve got used to looking at PD-L1 expression in esophageal cancers and we’re used to using CPS because we know that that’s using the microenvironment, as well as the tumor, and it’s probably a better marker for success of immunotherapy in these patients.
But the readout was really amazing. So patients who were treated with chemotherapy had a survival of about nine months, which is what we expect. And we added nivolumab, we improved the response rate, the progression-free survival and the overall survival, overall survival being 15 months, which was really fantastic. And so, this is a practice-changing trial for those patients. In the all-comers group, so unselected by PD-L1 biomarker on the tumor, the advantage was a little less, it was 2.5 months. And you got to ask the question, was that 2.5 months being driven by the patients who were expressing PD-L1? So I think there’s unanswered questions there. They didn’t present the data for the PD-L1 negative patients, and I would like to see that.
The other study was an Asian study, looking at pembrolizumab, and interestingly in patients, also a similar patient population with no 5-FU backbone, in the study. I really think that we’re all used to using a 5-FU backbone in Europe, also had positive results. So I think that we can see that there is a group of squamous cancers who are sensitive to immune checkpoint blockade, and these patients benefit from using this with chemotherapy. And it’s all about, I think, selecting the right group of patients. What we need to see is the CPS scores from the CheckMate 648 study. I think it’s been indicated but that has not yet been presented. Using TPS, about 50% of patients [inaudible] when CPS is used, so I’ll be interested to see what the regulatory approvals are.
Tobias Arkenau: No, that’s very, very important, and good point. My question, of course, we have a choice of two immunotherapy backbones, particularly one IO-IO and one chemo-IO. What’s your choice? Who gets chemo, who gets the doublet?
Lizzy Smyth: So I’m going to say, what would you treat your granny with test. I would say, I would give the chemotherapy doublet backbone. My concern for the nivolumab and ipilimumab is that, although there was a benefit in terms of overall survival, what we see, and what we’re used to seeing at this stage, is if we don’t use chemotherapy in these moderately sensitive populations, an early progression. So some patients are disadvantaged by using the immune doublet instead of chemotherapy.
So there may be, of course, valid reasons for some patients not to use chemotherapy, but I think you would need to have a conversation with those patients about maybe the 25 or 30% of patients who did experience early progression. If it were me, for my patients… And the approval, I think. There’s no approval yet of the immunotherapy doublet, even in the United States. And maybe our colleagues here can comment on that, but certainly the approval is there with chemotherapy. Similar to what we’ve seen in the previous study with pembrolizumab and at KEYNOTE-590. But certainly, both results are good for patients with squamous cancer, so they’re very, very happy to see these results evolving.
Tobias Arkenau: Nataliya, Susanna, any comments from the US? Is that practice changing for you in terms of… I mean, what would you [inaudible]. Approval is probably much easier to get than in Europe or the UK.
Nataliya Uboha: This is Nataliya. I absolutely agree with Lizzy’s summary. I think this was a great summary of the study and we’ve had some surprising approvals, I think, in the US. In adenocarcinomas that were approvals not based on biomarkers, and we know from prior studies and we know now from the publications that look at subgroup analysis, that these agents do not work that well in patients with lower PD-L1 score. That being said, this is a practice-changing study. And I absolutely agree with Lizzy that patients who are chemotherapy candidates, chemotherapy plays a role. We need responses, which is why you saw that overlap again, across all of the curves early on to the treatment of the disease. I think the other question remains what to do with all the second line studies that were done in patients who have not received prior immunotherapy, because I think those are becoming much less relevant and we really will need to look at combinations with IO past first lines.
Susanna Ulahannan: Yeah, I think I agree with both of you. The approval right now is chemo, so that’s what we’re going to use. But I think, with the data, with the immunotherapy alone, I think in those that are high PD-L1 expression, just to pick and choose where you think they can’t tolerate chemo, or also when they have very high expression, or patients, there are some patients that really doesn’t want chemotherapy. I think for all those type of patients, I think this is a very good option.
Tobias Arkenau: Yeah, and I agree. And one of the questions, obviously designing clinical trials, second line studies, how do we design them? That’s how you said correctly. I mean, the second line immunotherapy, there was a study, the RATIONALE 302, which was also positive against chemo, these become relatively irrelevant if you use upfront IOs. But how do we rescue the IO combos? Do we need to add… you know, we’ve seen very interesting data on tiragolumab, the TIGIT, combos in other tumor types like lung and gynecological cancers. Will that be the second line rescue, will be and again, I’ve seen some data. Some patients become actually extremely sensitive to taxanes. So is that the new chemo arm? What with irinotecan, the drugs we’re using as well in this setting? So, maybe Kai-Keen?
Kai-Keen Shiu: Yeah. So it’s going to be relevant if we get to talk about KEYNOTE-177, because everyone’s talking about maybe beyond pembro and doublet nivo-ipi and chemo. So I think the interesting thing is this, that I absolutely agree with Lizzy and Nataliya and Susanna. It is practice-changing for the squamous cell population. Well, my concern is that I think that platinum is great, but there’ll be a group of patients who maybe have had platinum within six months of, I don’t know, CarboTaxol or some other chemotherapy in the radical setting with chemo RT, they won’t want to get platinum. The ipi bit is important. I really think that CTLA-4 inhibition kind of fell behind a bit. Everyone was just going for PD-1, PD-1. But I think there’s something about giving CTLA-4 inhibition the exhausted T-cells.
And are we missing a trick here that if you give platinum with PD-1, yes, you get your increased response rate, yes, you get your maybe slightly better PFS, but then you lose a little bit of that duration of response. And we’ve seen this in some of the KEYNOTE studies in head and neck when they gave chemo [inaudible], chemo pembro and all those kind of things. And I think that I don’t know how you can integrate ipi to rescue those relapsed patients, though there was a nice talk, I think, by Toni Ribas in an education setting about using combos to rescue the patients that have relapsed on immunotherapy. So I do worry that we’re missing a trick here. And I think TIGIT [inaudible], all those combinations, really interesting, and to offer patients chemo-free remissions, I mean, forever. And wouldn’t that be so cool if you stratify those patients upfront?
Lizzy Smyth: I think that in particular TIGIT looks very good in squamous lung cancer. And I believe the early days in esophageal would also be good. And they’re looking at trials already integrating TIGIT into earlier stages of squamous cancer. So in the chemo radiotherapy frame. So I think it will really be by translation research. Won’t it? Because the drivers of resistance in these and acquired the same or different, according to histology, and according to site of disease. So I think really the translational outputs of, in particular, early phase studies and pre-treatment biopsies will be really important and informing those decisions in future.
Deborah Mukherji: I can see everyone nodding their head when you’re talking about translational studies. And I just wanted to jump in that you started with the fact that squamous esophageal cancer is a big problem in parts of the world where patients don’t have access to immunotherapy. So I think in terms of the global oncology view, those translational studies and knowing about the biomarkers and who really will benefit from either immunotherapy combinations or immunotherapy upfront is really where, academically, we should be trying to put more of our energy, if that’s possible.
Tobias Arkenau: Yeah, you’re absolutely right. And again, to Lizzy’s very early comments, we don’t have PD-L1 status. We don’t have TMB. We would expect TMB probably much higher than in the adenocarcinoma population. But I think one lesson learned is if you think about the 649 study in adenocarcinoma where actually the ipi-nivo arm was stopped simply because a higher dose of ipi… And Kai-Keen mentioned that it probably became a bit out of fashion, the use of ipi-nivo probably because the ipi dose was too high, too toxic. And so now on one milligrams per kilogram ipi and three nivo, that kind of regimen, you know, certainly without a better outcome and patients could receive treatment. And so I think very, very interesting data and certainly in this disease. Think about the squamous cell esophageal, where only 50% of patients make it to second line treatment. So if we stabilize, rescue them and offer them really newer treatments, great, great opportunity.
SECTION 2: Gastric cancer
Tobias Arkenau: Let me change gear. Of course, there’s another interesting data, which is the KEYNOTE-811, so, combining the pembrolizumab, Herceptin and chemo, versus Herceptin chemo FOLFOX backbone which kind of was interesting because it got a fast-tracked FDA approval based on response. What are we making out of this, Lizzy, and then the rest?
Lizzy Smyth: I think that we need to ask the Americans to comment on FDA decisions. Because sometimes I feel a little bit uncomfortable commenting on the regulatory decisions of other countries’ authorities. I’m not sure, having been to EMA, I’m not sure that we could get past EMA in terms of response. But I’m going to say this, maybe the perception that this is a premature decision based on response, but if we look at the data for immune checkpoint blockade in gastroesophageal cancer, response correlates to long-term outcomes. So even look at the long-term follow-up for ATTRACTION-2, which was the first study of nivolumab in chemo-refractory gastric cancer, the 12% of patients who responded in that study had a median survival of about two years. So we know that there is that correlate between response and long-term outcomes. And I’ll eat my hat if that study is negative. But I’m going to hand it over to the Americans to ask their opinion.
Nataliya Uboha: I share some of your sentiment that we’ve had some surprising approvals recently, but I think out of all of them, this was probably warranted. It was hard to ignore those waterfall plots, their response rate of over 70% with additional pembrolizumab. And also now coming out for two Phase 2 trials that showed similar responses, I think it’s difficult to ignore. And these patients have a lot of needs and this is a huge unmet need. And so, I think I am certainly going to start using immunotherapy in first-line setting in my patients with HER2 positive tumors based on these results. But, as I said in my discussion on this abstract during ASCO, we do need to wait for overall survival data and we do need more mature data. This was a pre-planned analysis, but only about half of patients were enrolled. I think the pre-planned analysis after about 260 patients, the total study is 650 or so patients. So there’s still a lot more data to be collected, but it looks good, thus far.
Lizzy Smyth: I’m interested actually in where this will potentially leave the studies which are looking at just, for example, MAHOGANY, which are looking at PD-1 and HER2 doublet without chemotherapy, because how high does this set the bar when you’ve got a response rate of 90%, for you to want to offer a chemotherapy-free option? I think that will be really… hopefully that’s a conversation that we’ll be able to have in future, but I think that will be really interesting.
Nataliya Uboha: I think the difference between the MAHOGANY trial, they are looking at the chemo-free arm, they are looking at very biomarker-specific patients population, they have to be PD-L1 positive or HER2 positive.
Lizzy Smyth: Yeah, that’s true.
Nataliya Uboha: In KEYNOTE-811, they did not require PDL-1 positivity, but amazingly 80% of patients or more are still PDL-1 positive. So I think there’s questions to be answered. But yes, the study with margetuximab is an interesting one to follow.
Susanna Ulahannan: Yeah. With the MAHOGANY study, just, I have several patients on it, and the quality of life is just, can’t compare it with a chemo arm. Both drugs are so well-tolerated, patients are really having a good quality of life. So it’s going to be a discussion with the patient, looking at the data, looking at quality of life, what are the goals of the patient? I think we’re going to get to that. It’s really a great time to be an oncologist, right? We have options. It’s not, this is it. And we don’t have anything else. I think it will be much more personalized and just see what the goals are for each patient.
Nataliya Uboha: And we may have to start teasing out things like how long does it take to get to the response, right? All of these things that become important to you, how deep the responses are. Dr. Janjigian did talk about the depth of response in her presentation, something that we actually didn’t discuss before in these tumors because the options were so limited. So I agree. I think it’s good to have options and you’ll need to learn how to sequence them too.
Kai-Keen Shiu: I do want to jump in there. I recruited quite a few people in the UK for the KEYNOTE-811, and I think in the last meeting, ASCO GI, we said that one of the problems is these people are quite sick and they do need an early response. So I definitely saw extremely good response. I wasn’t sure whether it was because I just picked very fit people because they’re PS01 and therefore they were going to do well on chemo, but I really was encouraged by that. And I’ve got some patients I think must be on pembrolizumab because they’ve got some minor effect. And they’re doing great. My concern, as you said, was that it was a read of about 260 patients, or actually, I think was about 800 patients, they’ve extended the cohort. And if you look at the response rate, it wasn’t quite as good as 90, it was 74% versus 50%.
The good news, I agree with Nataliya, was that when you look at the Yelena study in Phase 2, at least it wasn’t much worse than that, because often that’s what we see isn’t it? You see Phase 2, it’s amazing. And then in Phase 3, it’s like 20% less response rate. And I think what’s interesting is the PFS was exactly the same. But again, this is what we saw in the squamous population, the OS is going to pull out later and you’re going to get, I think, as Tobi has said, there’s an interesting study in lung where second line docetaxel after first line pembro, response rates were 22% versus 8% in KEYNOTE-010.
So that’s probably what’s going to happen, I think, in the first-line pembro studies is that the second-line chemo, or even rechallenge of chemo. So some of my patients who’ve had chemo plus pembro plus Herceptin and then progress, and I get them back on chemo, they’ve had fantastic responses. And I think there’s something about that. So in a way, the Americans jump in, they make the bold statement, sometimes they’re absolutely right and they absolutely, it is great. Sometimes they’re not quite there, then I hate to say it, the rest of world deal with the translational stuff to catch up with them, but they usually make the right decisions because that’s the way. And in some ways, it’s great that you have those FDA, kind of, early orphan indications.
Susanna Ulahannan: I completely agree, the stop and go approach. I think when people stay on for a very long time, that’s very compelling.
Tobias Arkenau: Okay, great. Really great discussion.
SECTION 3: mCRC in 1st-line setting
Tobias Arkenau: And I want to shift gears a bit into colorectal cancer. Although, you see the last 30 minutes, great, exciting, really practice changing treatments in esophageal and gastric cancer. Colorectal cancer has been, for me at least, more looking into biomarkers, a bit more detailed, some studies we were waiting for, they just probably confirmed what we would have expected in our day-to-day practice, but seeing nonetheless very important that we have them out and confirming what we thought about them, particularly about the RAS wild-type BRAF mutant. And Deborah, any views on that, and your view on practice changing, what do we need to do? Do we need to do triple regimens upfront or do we do sequential? All these kinds of questions. Including, of course, the chemo breaks and maintenance questions. So, a big ask for you to summarize your views.
Deborah Mukherji: Sure. So I think moving to colorectal cancer, we have less exciting data at ASCO this year. But, as you mentioned, we’re trying to refine how we use the tools that we have. So the first trial that we saw was a randomized Phase 2, the DEEPER study, a randomized Phase 2 study from Japan. And that was looking at the question of using triplet therapy upfront. So FOLFOXIRI, plus cetuximab or bevacizumab in patients with RAS wild-type colorectal cancer in the first line. And this used an interesting endpoint. So we’ve been talking about depth of response and correlates in immunotherapy, but in chemotherapy, we have this impression that we like our patients to have an early and a deep response to treatment, but we haven’t really conclusively proven that this definitely correlates with overall survival.
And this trial chose an interesting end point of depth of response. And they were looking and the trial was actually positive. So the arm randomized to FOLFOXIRI plus cetuximab had a deeper response on average, but actually there was no difference in other markers such as overall response rate or resection rate, and no difference in the preliminary data for PFS and overall survival. So the question that was discussed is really does this change our management? Probably not. The majority of these tumors, as we see in real life, were left-sided tumors. But again, as expected, the patients with right-sided tumors did less well with the addition of cetuximab. So I’m not sure it really changes our clinical practice.
I’m not sure if the panel could comment when they would choose to use FOLFOXIRI as a first-line treatment in their patients with colorectal cancer. It’s not something that we’d commonly do in all the patients who have RAS wild-type disease. Perhaps I can ask someone to comment on when they use this triplet treatment, when to intensify chemotherapy, perhaps the patient that needs a really rapid response or the patient who we feel has lots of symptoms due to their disease. Perhaps I could ask Kai-Keen, in which patients are you choosing FOLFOXIRI upfront for in colorectal cancer?
Kai-Keen Shiu: Yeah, thanks for the question. I think basically there’s a question of less is more and this one is more is not more. So I think that in the end, with now, all the targeted potential agents in first and second line, I’m far less keen to give someone upfront FOLFOXIRI, even in a BRAF mutant patient now, actually. I think that it depends on the burden, I’m talking about the tumor burden and the patient’s fitness and things like that. But even in a really fit patient, necessarily, I’m not sure I would rush in. I standardly give one cycle of FOLFOX, get all the profiling done and then add in the chemo, plus maybe bevacizumab and-or other things on cycle two or three. And no one’s ever done a trial of that, but I think it’s generally good, because it manages the patient expectations, and also saves things that later.
I do think that all in is useful. And we’ve shown in the OLIVIA trial, we’ve shown in the other studies, you give a load of chemo and somehow the R0 resection rate doesn’t improve. What are we actually trying to do for these patients? So personally, I think that when you say you’re giving targeted therapy with FOLFOXIRI Avastin, that is not targeted therapy. That is hedge your bets like hell, okay? And then hopefully you get a bit of a response and survival and stability. And then I would deescalate massively but I don’t know what the other panelists think. I’m really kind of… I don’t like… I do give FOLFOXIRI, but I don’t give it really upfront on cycle one or two. I try to think about it and then add it in.
Lizzy Smyth: I think, unfortunately often the patients who need the response, most are those who are least likely to tolerate it, isn’t it? So we do use, I do use FOLFOXIRI for BRAF mutants depending on the situation. There’s a lot to of BRAF mutant patients who have bad perinatal disease and might not tolerate FOLFOXIRI. And I’ve also used it in RAS mutant patients. We don’t have access to bevacizumab in the NHS. So ultimately, if I did, I might be more comfortable giving them a doublet with bevacizumab, but if we don’t have that choice, I think using a triplet is okay for young patients. And sometimes in the neoadjuvant setting, to de-bulk really horrible tumors to get them to surgery. And sometimes I have performed CRS and HIPEC, actually, for BRAF mutant patients. But it’s not a standard, I agree. I would use doublet much, much more frequently than FOLFOXIRI.
Tobias Arkenau: That’s very good. I was very excited to see the, really look forward to seeing the molecular analysis of the BEACON study. I was somewhat a bit disappointed the way it was presented. I’m not sure… Deborah, any views on this? It was the comparison doublet versus triplets. I thought we left that debate already, but maybe your view on BEACON and the molecular subtype analysis.
Deborah Mukherji: Sure. So these were patients who had whole transcriptome sequencing of the initial tumor specimen. And we’re trying to really tease out which of the patients that really needed the triplets, the addition of the triplet therapy. And I think that their conclusion was that they did find certain molecular subtypes, the more immunologically inflamed subtypes, perhaps, which have a benefit. But I think the problem is that the access to these types of whole transcriptome sequencing is going to be limited. I don’t know if our colleagues in the US could comment. So we certainly don’t have access to that sort of thing on a clinical basis. Is that something which your patients would have access to, to divide them as a biomarker into who should have triplet rather than doublet therapy? Perhaps I can ask Nataliya.
Nataliya Uboha: It is not part of the standard of care right now. So no, we would not have that in clinic either.
Deborah Mukherji: Yeah. So I think that’s probably far off, although it’s an aspiration for the future to try and better define those molecular subtypes, so who are really going to benefit from our toxic and expensive combinations of therapies. And I think that this is probably something that needs a little bit more work. And some of the circulating biomarker work is looking a lot more interesting, I think, because we know that we have many changes, we have lots of, potentially not the BRAF mutant patients, but the RAS wildtype patients, lots of evolving mutations, which are going to be important to detect. So I think my prediction is that the future would be in circulating biomarkers to refine our treatment strategies for colorectal cancer.
Tobias Arkenau: Yeah, I must agree. I mean, I would have expected, even in an analysis like this, we have co-mutations, one of the ones who don’t respond at all what patients, despite having the V600E mutation. I was missing that completely. And it was a bit like bringing triplet regimen back into the game and try to identify… I mean, it’s important work, I don’t disagree, but I would’ve, probably for an ASCO presentation, expected a bit more practice-relevant…if I’m sitting in my genomics review board, I want to know, what is my V600E plus co-mutation X and Y doing, APC, p53. And we know that those patients don’t do well, they progress even on the BRAFs, cetuximabs, doublet after three to four months, versus, you know, where are the good ones, where are the 10 months PFS. So that’s something I… Again, think about this. These are very important translational research studies where lots of tissue is utilized. So hopefully there’s tissue left to do these other analysis. They may be not that great, but I was a bit more hopeful that we get more analysis. We need to, as you said in gastric cancer, in colorectal, we need to move on from that. We have the tools or toys to molecularly identify colorectal cancer, and I think we really have to move that on.
SECTION 4: mCRC maintenance therapy: when less is more
Tobias Arkenau: So there were other studies again in the oral presentation session, less is more maintenance therapy. And again, Deborah, Susanna, maybe you want to comment on this PanaMa and then FOCUS. Kai-Keen, you were the MRC UK fellow on FOCUS. You were funded, this is your career, FOCUS, so tell us about some of those datas and how this is relevant in the context.
Kai-Keen Shiu: So, let’s start with FOCUS4. So at first I want to say, it was a brave endeavor. Okay? I mean, FOCUS4 was, yes, funded massively and I was a fellow for about 18 months for them. I think that I probably learned more about how not to do basket studies from it. And I still learned a lot. So it got me into my field, and how maybe you just can’t do everything all in one go and you have to regulatory approve everything. And even I think the modal studies struggled and even in America, they struggled to do their study. But I think that the FOCUS4-N group was interesting to be presented. I think that it was a bucket arm because we were trying more to push the BRAF arm, which didn’t pull through, the all wild type arm. And now there’s some really other interesting sub arms which will eventually get published.
We changed the design of the study. So, I think you’ve got to think about this. The only analogy I could think about when we were thinking about was the CAIRO3, which even that is not necessarily practice-changing, we had this big thing, is how much does bevacizumab add to capecitabine, there wasn’t a capecitabine only arm. Would this be like a kind of CAIRO3 without the RAS? It didn’t really turn out that way because we completely skewed the types of patients who ended up in the FOCUS4-N arm. I think what was really interesting was, and you’ve got to remember when you look at PanaMa versus FOCUS4-N, the PFS addition, it looks minor because it’s like, oh my god, I need four months, but you’ve got to remember, they had a lot of induction chemo. They had about 16 weeks of induction chemo.
But actually it was interesting that there was some difference, whether it was clinically meaningful, I don’t know. And I don’t know if it’s necessarily practice changing, but what’s the flip side was CAIRO3 kind of said, in the responding patients, you should push maintenance, actually both in PanaMa and in FOCUS4-N, it says actually, you shouldn’t. And I liked this because it means the responding patients should have a break, a proper break. As in, if you’re clever about this, you don’t even need to stratify to ctDNA, or anything like that, you just say, look, these responding patients are probably going to do well. You can give them a six, eight, 12-week break. And the ones who need it are the ones that only achieve stabilization.
So that’s a roundabout way of saying that neither, I think, PanaMa, which someone else can comment on the PanaMa trial, because I massively respect Dominic as well, who’s kind of my age and feeling his way around. I think that there was, as a good endeavor, I don’t think it’s going to practice change. It already kind of tells us what we’re going to do in maintenance, but it’s good to get those studies out and discuss that oral presentation.
Deborah Mukherji: I think it’s important because this is a question which a lot of patients are having quite toxic maintenance treatments. And this is really the question, is it really doing them any good? And there’s a lot of, sort of un-evidence-based practice, which goes on out there, and patients getting a lot of toxicity, particularly with drugs with visible side effects, which affect the patients. So I think this is really important data to get out there and to get published.
Kai-Keen Shiu: It is important, but I’d like to, again, ask Susanna and Nataliya because these kind of first-line studies are in the NHS, right? And we have only access to EGFR, let’s be honest, in the NHS in the first line. So we are pushing our patients on long-term frontline EGFR maybe with benefit in some, maybe not. And it came up again in KEYNOTE-177, everyone should get access to immunotherapy. Well, not everyone in the world can get access to both first-line and second-line, and on relapse immunotherapy.
So I think that this is the difficulty, isn’t it, that if you have a really great healthcare system where you have got approval in every line, you can do rechallenge and second line, that’s fine, because you can think very far ahead of yourself. But if you have limited options, we normally still say choose the best option and first-line because that’s probably the line that is going to give you that benefit in long-term because you don’t maybe have access to the rechallenge of EGFR. So again, just want to ask Nataliya and Susanna both in your cholangio field and things, do you have that feel that because regulatory things get in the way, you can’t actually do everything you want to do, even in the clinic.
Nataliya Uboha: You know, in the US, during the treatment of colon cancer, we have access to all of the approved in the US agents, right? Bevacizumab, anti-EGFR agents, Lonsurf, so…and in our practice at UW, I think we concentrate a lot on sequencing these therapies. We actually have an investigator-initiated trial led by Dr. Demi who is looking at first-line anti-EGFR, looking at patterns of resistance with circulating biomarkers, and then trying to even reuse the anti-EGFR agents down the line, although traditionally, everybody started on first-line chemotherapy. So that’s not as big of an issue here. And really, my strategy with colon cancer patients, who are not resectable, of course, who are not candidates for ablative local-regional therapies to the liver is, is to expose them to as many therapies as possible and try to sequence them to my best ability.
So some of the maintenance trials, I thought they were interesting because it’s always a struggle to keep patients in chemotherapy for a very long time, and people want treatment breaks. And so I thought it was nice to see some of the data that justifies treatment [inaudible] because I’m always worried about stopping chemo. And I think I’m biased by the fact that most of my patients are upper GI patients. And we know that stopping chemotherapy in that patient population is probably not the right thing to do. And a lot of patients deteriorate quite rapidly.
Susanna Ulahannan: Yeah, I completely agree. I just feel like, just looking at my patient population, we see all these young patients, more and more I have patients that are in the twenties, thirties, forties, right, with young families, and keep asking, they want a chemo break. And so I really feel like this gave, you know, some more meat, that we can give them chemo breaks. And I think it’s very important. Because these patients, they stay on treatment for years and years and years, and just to balance quality of life, versus longevity.
Lizzy Smyth: Isn’t it a decision that needs to be made on an individual patient level, right?
Susanna Ulahannan: Absolutely.
Lizzy Smyth: Because I think absolutes, we shouldn’t have them, because some patients will want to stay. I have some patients who would be on FOLFIRI and cetuximab for three years and they wouldn’t hear of stopping it. Whereas for some patients, three months of treatment is enough because they don’t like to come to the hospital. They maybe have a low disease burden. I think that there are so many trials that often you can find evidence to support whatever argument that you to make. And for me, if a patient’s disease is not an immediate threat to their health and they wanted to have a break, I think we need to be sensible about these things and really have a shared decision-making, but also they do want us to tell them what to do, I think. And I’m comfortable with either approach, I have to say, depending on the patients.
Tobias Arkenau: And we need to have the, I guess, the honest discussion and debate with the patient. Again, it’s so easy to continue the drug and sign the chemo form or press a button, hey, chemo gone. It is this honest debate, actually, that it doesn’t affect at least… We haven’t seen any overall survival benefit of continuing this treatment. And Susanna, you said correctly, we see increasingly younger patients. And of course it’s our own conscious. We want to keep them alive, keep them on treatment. But really, that says result in better outcome. I think some of the debates on this, was not only in GI at this year’s ASCO, was about this less is more, do we need to have as well, as an oncologist, the responsibility to have these honest discussions about actually continuing on beyond cycle 10 and whatever may not be the right thing to do. And we rather have a strategy to reintroduce you. And again, the debate, I mean the optimal studies were, how old are they? About 10 years. It feels a bit like a second revival, but we have been there before. So it’s nothing new, actually, we know this, and we just need to implement this.
SECTION 5: Biliary tract & pancreatic cancers
Tobias Arkenau: Okay, biliary tree cancers. I found again last year, big, obviously, presentations on FGFR and IDH1. And so this year, Nataliya, went back to chemo, and I think a very relevant question, probably similar to the squamous cell esophageal population, these patients are often poorly, they can’t tolerate the second line treatment. We waited pretty much up to just recently for defined second line treatment and here we have one presented with Nal-IRI and 5FU. Your view on this and are you using it in day-to-day practice already?
Nataliya Uboha: So I’m actually planning to use it for one of my patients next week. I thought this was a great study. So for bile duct cancers, first-line treatment remains gemcitabine and cisplatin, so the platinum agent. There was an ongoing Phase 3 study gem-cis abraxane versus gem-cis but there is also a mature [inaudible] patients will not be candidates for triple therapy in first line. So then we get to second line. And we were all very excited about all of the biomarker-based studies. And we talked about them up to GI ASCO. It’s great. However, it’s at most 25 to 30% of patients in whose tumors we find something. So that leaves 75% of patients, assuming we have limited treatment options.
And ABCO6 was an important trial. It was a Phase 3 trial that looked at FOLFOX versus best supportive care. It was a positive trial. The signal was there, numerically the numbers did not look that great, right? Especially in terms of PFS. And you looked at oxaliplatin after progression on cisplatin. So also there’s two platinum agents. And so, I was excited to see this study. This was a Phase 2 trial, Phase 2B trials opposed to Phase 3 trial versus ABC06. If you look at the number of patients, actually, it was almost identical in each arm. It was 80 patients in each arm. But in this study, they actually compared 5FU alone to 5FU plus Nal-IRI. Similarly to this study, NAPOLEON study, that was done in second-line pancreatic cancer.
And it was a positive study, a significant improvement in OS, significant improvement in PFS. PFS was a primary endpoint. Of course, they can’t compare study to study, but numerically it looked better than FOLFOX. And I think for me, looking at their response rate, looking at OS, looking at the fact that would be a changing mechanistically one chemo agent, platinum agent, to a non-platinum agent, makes me more excited about this regimen as a possibility for my patients in second line. I think the Phase 3 study is going to be tough because it’s a rare disease type. And I don’t think they’ll have the… It will take years to complete. But this was a great study.
Tobias Arkenau: Yeah. I must say, I use actually the Nal-IRI more often, actually, its better in pancreatic cancers. So these kind of FOLFOXIRI first-line, I have completely stopped this and do effectively gem, Abraxane, then Nal-IRI, then FOLFOX, simply from a toxicity point of view. And so, I think there’s a bit of a resurgence of this in biliary cancers now as well, so quite interesting. Anyone, this is practice changing for you or just, I think it’s solid enough. It’s a Phase 2B study. I probably don’t need to see a big randomized Phase 3 study.
Nataliya Uboha: It’s not FDA approved though.
Kai-Keen Shiu: I do have a question about the Nal-IRI bit. So again, Deborah was saying real-world. If we wanted to go cheap as chips, you would give them FOLFIRI, right? And there was some data around when the triple negative breast nab-paclitaxel with atezo versus why don’t we do Taxol, right? And then is it something amazing about it being a lipid or not? So I just wanted your view. Because we don’t standardly give… There are some trials for FOLFIRINOX versus cis-gem for neoadjuvant biliary tract, but I think it’s a negative, I think it’s a negative study. So where is suddenly that the oh, let’s just go with not only irinotecan, which has, I think, limited… 5FU yes, absolutely, limited evidence with irinotecan, but let’s go with it. Let’s go with a Nal-IRI. What do you think about that?
Nataliya Uboha: I think irinotecan does have activity in this disease based on small studies. It’s a pancreatic biliary disease. Again, you’re bringing out the point, of FOLFIRI and pancreas, we have some overlapping biology and probably sensitivity to chemo. So this was likely a company-sponsored study, I think with liposomal irinotecan. I don’t know how much benefit liposomal irinotecan provides over irinotecan here. I think there’s some preclinical data showing that the tumor has… Well, I know there’s preclinical data showing that the tumor has higher exposure to the active ingredient of irinotecan in liposomal disease, [inaudible] toxicities. But I don’t think we will ever have a definitive answer. And I think it is very reasonable to use FOLFIRI in the countries and communities where access to liposomal irinotecan is limited.
Susanna Ulahannan: And now, in pancreas cancer, they have their ongoing trial with switching the irinotecan to the liposomal irinotecan. Not a head-to-head study, but it gives us a [inaudible], we’ll see what’s happening.
Nataliya Uboha: Yeah. It’s a first-line Phase 3 study with gem abraxane. I actually have an investigator-initiated trial sponsored by Ipsen and it looks at this combination in first-line gastroesophageal, that we opened last year. And I’m very actually impressed by the tolerance of those regimen.
Susanna Ulahannan: Yeah, I agree. And I have patients on that trial as well, the Phase 3 trial in panc. And overall, we are all used to using the Nal-IRI in panc so it’s easier than a totally new drug if we know how to treat our patients and what to look for and handle these patients also in their community. There is a familiarity with the combo.
SECTION 6: Emerging therapies
Tobias Arkenau: Susanna, we’re ending closely or finishing in the next 10 minutes. Tell us what’s, for you, the most exciting, new drugs, Phase 1 that made it into Phase 2, what is the new molecular target in colorectal, upper GI, your impression, your views.
Susanna Ulahannan: Yeah. So I was very excited about the DESTINY-CRC01. Our breast colleagues are ahead of us. They got their approval in 2019 and then we have the gastric GE junction approval, December here in 2020, in January 2020. And so then now we see the data from colorectal cancer. I thought it was interesting that they did a three-arm study looking at HER3-positive, or two-positive with FISH, ISH-positive versus two positive and one positive. Just thinking that this is the antibiotic drug conjugate, we just leave the drug to the tumor and it’s more the chemo and not a targeted pathway. But there was no responses in two plus or one plus, but all the data was in three plus.
Lizzy Smyth: That’s really interesting because the HER2 low in gastric cancer had a response rate of 24%. But isn’t that to do with how they’re categorized differently the HER2 status in colorectal versus gastric cancer, right? The actual scoring systems for a proportion of cell that need to be positive are different, aren’t they? So I wonder is that why that inflect that? I didn’t know that. That’s really interesting. It’s a beautiful paper, I was making a presentation on this, actually, that shows, I think it was in maybe [CCOR] a little while ago, that shows the bystander effect of trastuzumab deruxtecan, and you can see the actual [inaudible] is in better part diffusing into the tissue into the non-near positive cells, HER2-positive cells. It’s a really interesting drug.
Susanna Ulahannan: And just looking at the waterfall plots, the study is just stunning. And I mean, so they did… They had to be KRAS wild-type to go on the study, but with the response rate of more than 45% in a heavily pretreated cohort patient population, and an overall survival of more than 15 months, I thought the data was stunning. We’ll see how it goes in a later phase. But they are looking further into this. And also, the other thing I was thought was interesting, so in breast, they have the lower dose of 5.4, but both in gastric and now in the CRC population, they’ve chosen the 6.4. And so, I thought it was interesting that they are actually going to compare them, head-to-head, with the lower dose versus the higher dose, especially in view of the ILD with this drug. The waterfall plots are amazing. The efficacy is great. But then we have that 10% of ILD. When we look at the breast data, which is much bigger, they had about 13% of our ILD.
Nataliya Uboha: Well actually grade five toxicity in this study, right? Yeah, within gastric cancer, the majority of them were wild ILD.
Lizzy Smyth: Yeah, absolutely.
Nataliya Uboha: But these were three death, I believe.
Susanna Ulahannan: Yeah, three deaths.
Lizzy Smyth: I think it’s proportional to the duration of time on treatment, the risk of ILD. So it’s unfortunately, sadly by definition, likely to be shorter in gastric cancer.
Susanna Ulahannan: Oh. That’s a good point. Although, they did see some of them pretty early on starting quite early.
Nataliya Uboha: Did they?
Susanna Ulahannan: It can happen anytime, that’s really the problem. But I think lowering the dose is probably a good idea to see if we can get the same efficacy with the breast dose that was used. And just using this drug in gastric cancer, I think lowering the dose to 5.4 hopefully will help the tolerability, from that standpoint.
Lizzy Smyth: It would be interesting to see the DESTINY-2 results, I think, in the Western populations. So I think we’re all looking forward to seeing those and seeing whether the efficacy is equivalent to what we’ve seen in the New England Journal paper, which was Asian patients.
Nataliya Uboha: Which is, again, another FDA approval in second line [inaudible] based on that Phase 2 data in third line Asian population.
Lizzy Smyth: I don’t know how you guys get people on trials because you’ve got all these approvals.
Susanna Ulahannan: And it’s already on the NCCN guidelines.
Nataliya Uboha: Mm-hmm (affirmative). It was approved right around GI ASCO. I have a patient on it who is responding. It’s a great drug, but again…
Lizzy Smyth: Yeah, we’ve got patients coming from all over the country because we put a fair number of patients on that trial and it’s great to use it. So, really looking forward to seeing the results.
Tobias Arkenau: Anything else, Susanna, anything from the drug development, early phase GI that you found particularly interesting?
Susanna Ulahannan: Yeah. So we talked about pancreas cancer and really a high unmet need there, but I really liked the NRG1 fusion is in a cetuximab, the bi-specific HER2/3 antibody. So excited to see that data and to see those waterfall plots and just this patient population, I think it’s overall 0.2% of solid tumors will have this NRG fusion. So a very small population. It’s enriched in pancreatic cancer patients who are younger, who have KRAS wild-side. So again, a very small population. But the importance of molecular profiling and just finding those patients [inaudible], the NRG fusion, just remarkable responses, but very few patients that would benefit. But I thought that was probably the one I got most excited about.
Tobias Arkenau: Well, the problem is that these NRG1 fusion results sitting in our inboxes for three or four years, no one is reacting. So we’ve recently found a breast cancer patient, three years had a big foundation medicine panel, KRAS panel. No one has reacted to that. And so by chance, we found the NRG… Well, it was there, but then someone looked at it in our genomics review board. So with patients on now for more than a year, we did pretty much no toxin, great responses, this being a breast cancer patient. Really interesting.
But I think it just highlights that… Pretty much every day we get new targets and we need to look at our 300 gene panels we use so often, and often don’t understand this, that those big panels have to go through genomics review boards, so at least people understand genetics and the impact of those, and that’s really probably the lesson learned. And then suddenly you find these. We have just in the last two weeks found two patients with HER3 mutations, which potentially also respond to that drug. And so wow, here we are. So very interesting.
Susanna Ulahannan: And also, with this NRG1 fusion that they find it much more with the RNA sequencing rather than the DNA sequencing. And so, it’s getting more and more complicated.
Tobias Arkenau: Absolutely. Good. I think we are over the hour. Any super highlights I forgot to mention to highlight? It has been a great ASCO. Although, unfortunately the second time virtually. Hopefully next year we see each other and do from VJ, I guess VJOncology will have a nice roundtable the next time, we’ll be sitting all in one room and have that discussion live. So thank you again for your time this afternoon. Thank you VJOncology. And really looking forward to meet, talk and exchange these new findings in the very near future. Thank you, guys.
Lizzy Smyth: Thank you.
Nataliya Uboha: Thank you so much.
Susanna Ulahannan: Thank you so much, nice to see you.