Targeted Therapy for Colorectal Cancer (CRC) — Wells A Messersmith, MD

DR MESSERSMITH: My name is Wells Messersmith. I’m a Professor and Head of the Division of Oncology at the University of Colorado Cancer Center. I also serve as Chief Medical Officer for Oncology Services for UC Health, and I’ll be talking today about targeted therapy for colorectal cancer.

We’ll go ahead and get started with a paper that got a lot of attention nationally, and I think many of us received lots of messages from our patients wondering if this pertained to them. And of course, unfortunately, it’s actually fairly rare to have an MSI-high rectal cancer, but we do see these patients.

But what an amazing story. This was using a checkpoint inhibitor called dostarlimab, and it was administered every 3 weeks for 6 months in patients with Stage II or III rectal cancer. And what’s different about rectal cancer as opposed to other cancer types, of course, is that sometimes patients who are unresectable end up needing to have an ostomy the rest of their lives. So if you’re able to handle them in a nonoperative management type of way, in a medical way, that can have an incredibly life-changing effect.

And of course many of us have had patients who steadfastly refuse to have an ostomy and basically say I’d rather die than have an ostomy. Or they have poor anal function and don’t have continence and have to wear diapers the rest of their life, so this is actually a major breakthrough.

The bottom line on this, and there are actually over 20 patients now, maybe even close to 30, as I’ve heard Andrea give different talks at different times, but really had incredible efficacy here. And you can see the treatment portion of the study followed by near-complete response and complete response, and basically everybody responded. I think later on this 1 light blue bar, number 12, ended up having a complete response as well.

And so it’s pretty rare for a 13-patient study to hit national news, but it did because for these patients, again, it’s pretty lifesaving.

And this is from the publication, and on the left you can see the demographic table. I mean some of these patients even had T4 disease, and 15 of them had positive lymph nodes. And if you look at baseline, which is the first column of pictures, 3 months and 6 months, you really see these impressive local responses. Endoscopy basically can’t see the tumor anymore. And as you look at rectal MRI and PET scan you can see that initially you see this PET-positive fairly large mass in the rectum, and then it basically goes down to nothing.

Now of course these patients do need to be followed, which they will all be followed closely with a nonoperative management protocol, but at this point you’re able to spare these patients surgery and just keep a close eye. And so this is incredibly encouraging.

On the left graph you see biopsy specimens before and after, and you see the viable tumor cell content. Of course part of this will be sampling in terms of what they’re actually able to sample, but again you can see that the viable tumor over time comes down very nicely.

Now the kinetics are a little different patient to patient, and also it would depend on when they’re able to carry out the biopsy. But very nice results there in terms of tumor response. And one explanation could be that you’re getting increased immune activation at the site of these tumors.

And at the top bar graph you see the before and after looking at CD8 T cells and also looking at CD20 both in the epithelial compartment where the tumor is but also in the stromal compartment. You can see actually many of the changes are mostly stromal.

DR LOVE: I guess one of the things about this is this is not like what you see in metastatic MSI high. I mean plenty of those patients don’t even respond let alone have a complete response. And I know, as you say, it’s a big — when I first saw this I was thinking oh, small number of patients maybe, I don’t know, but it just didn’t really resonate with what I understood about this situation.

Do you think it could be the fact that it’s a primary as opposed to metastatic? I know there have been some attempts to look at other sites, colon for example. What happens when you give anti-PD-1 to MSI-high localized colon cancer or upper GI cancers? I don’t think everybody responds, do they?

DR MESSERSMITH: No. Not everyone responds, and there does seem to be something different about these primary tumors because we just wouldn’t expect you to bat a thousand, and whether or not it’s because you still have the lymph nodes in place, you haven’t had some kind of big surgery. All of those things could come into play, and so I’d say the response here is higher than we expect to see.

That being said, even in the advanced-disease setting, even though the lesions don’t go away completely, you often have patients who’ve been treated for 2 years with immune therapy, there’s still a small lesion there, but we just leave it alone because historically we found if you resected those you often just found scar.

So exactly what’s going on with metastatic patients I think is a little harder to say because we don’t go in and resect every little lesion that we saw in the beginning. Because I have patients that I put on immune therapy studies way back when where they’ve been off immune therapy now for several years. They still have some lesions present, I still see them every 6 months or so, but those lesions haven’t changed in many, many years. And I think the patients are cured, and I think most of us have had those types of experiences in MSI-high cancers. And whether it’s gastric or biliary or whatever you have you often see these incredible responses.

But I do think there must be something different about the immune milieu, if you will, of a primary tumor and perhaps the presence of lymph nodes that lends itself to having an even more impressive response.

DR LOVE: I guess it could be the rectal location or microbiome. What about MS-stable rectal cancer? Have IOs ever been given there alone or with nivo or with regorafenib for example?

DR MESSERSMITH: Yeah. So people are starting to look at that. There’s trials that are in various stages of development. The issue with the drug, I’ve actually seen proposals because as you know there is some activity of a checkpoint inhibitor, for instance, and tyrosine kinase inhibitors, right?

DR LOVE: Right.

DR MESSERSMITH: So there’s some proposals to look at that in patients who have unresected primary tumors. The problem is the VEGFR activity. We worry about perforation and bleeding when you have a tumor in place that’s invading much of the wall of the gut.

DR LOVE: Right.

DR MESSERSMITH: So we’re going to have to think about that from a safety standpoint. And we’ll just have to see how this story plays out. But there does seem to be something different about that preoperative setting that lends itself to efficacy of immune therapy, even in MSS tumors as well.

DR LOVE: Any reason to think the location could have anything to do with it?

DR MESSERSMITH: You’re right. I mean it’s a different microbiome, it’s a different embryonic origin, so I think that certainly a possibility, although I would say I have had remarkable responses at the primary tumor site in many different tumor types.

DR LOVE: And you’re saying the Memorial group now has 30 people. Again, they’ve all responded?

DR MESSERSMITH: This was verbally said on the podium at presentations, and yeah, they’re still batting a thousand.

DR LOVE: Wow. Wow.

DR MESSERSMITH: Yeah.

DR LOVE: So interesting.

DR MESSERSMITH: Yeah, but I would say this — unfortunately this is a very rare occurrence. I mean in Colorado we see close to a thousand cases of colorectal cancer a year, and we have very few of these. I think it’s no mistake that a big, big place like Memorial is able to get this done. So it’s very rare but again shows that we really have to do reflexive MMR testing, and as I do second opinions I still occasionally will have cases where they haven’t done the MMR testing. So from a patient perspective and a provider perspective the key thing is to get that done.

Looking at dual blockade, so the NICHE-2 study. This was really more of a pilot study in a sense. They gave a dose of ipi and then 2 doses of nivo, so kind of different from the Memorial experience where they gave the 6 months. And so it was all around safety and feasibility. And I do think that we really haven’t had safety signals with regard to surgery after immune therapy, which is great, and I think that lends itself to preoperative approaches as opposed to agents that have VEGF activity or things where you might have to worry about perforation, bleeding, and other issues.

But here if you look at a major pathologic response you see that they had that in 97% of patients. 67% had a pathologic complete response. And as I said, they did not seem to have increased surgical complications. And if you look across going from low risk to high risk you see roughly the same pathologic complete response rate no matter what the stage is. I mean obviously these are small numbers, and there is some variability in the numbers, but there doesn’t seem to be any big differences. So I think further food for thought in terms of immune therapy in this setting.

I will say we tend — instead of dual checkpoint we tend to give single agent as the Memorial group did, and we tend to give it for a longer period of time. I don’t think we need to give 2 doses and then rush into surgery. We think actually you’re better off giving it a little more time. So we tend to use the Memorial approach as opposed to the NICHE study.

Looking at KEYNOTE-177, so this is the first-line immunotherapy study, and you can see that patients were randomized between pembro versus a whole host of investigator choice therapy, and then there was an optional crossover. And these are the updated survival curves that were published by Luis Diaz in Lancet Oncology. Luis and I were fellows together, so it’s always nice to see him publish a nice paper like this. And you can see that the — basically the updated results with the checkmarks going way out, past that 3-year mark. It still showed really nice hazard ratio in favor of the pembrolizumab group with a hazard ratio of 0.74.

You see that initial difference in the curves as therapy starts, probably reflecting the kinetics of chemo response. The chemo tends to respond a little sooner, then the curves cross really at around the 6-month or 8-month mark, and you see the advantage, and sustained advantage of immune therapy.

Looking at the various subgroups. This is the forest plot, and you can see that really across all the subgroups you get benefit. One of the things that I’ve always been fascinated by is the fact that BRAF patients — we think of BRAF as kind of this overwhelming biomarker and causing this aggressiveness, and yet if you’re BRAF, MSI high it’s tamed by the immune system and kind of gets outweighed by the immune system. So that’s actually something that’s nice to see. But you can see that really there was no difference.

DR LOVE: I don’t know if you know, but I think it was in the last couple weeks they had the 2 big Phase III trials in endometrial cancer, of course they have a lot of MSI high there, and both trials very similar results, but it was chemo plus IO. They didn’t even have an IO alone, so I don’t know what they’re going to do. But it did bring up the issue, because we talked about it there, of what do you do with a patient with MSI high who either is very, very symptomatic and really can’t afford to have progression or maybe they have liver mets and they need it to be shrinked. Would you add chemo plus IO to a patient like that?

DR MESSERSMITH: So there is a cooperative group trial looking at this, chemotherapy plus IO in colorectal cancer, so I think we’ll have the answer soon. In my own practice, if I’m waiting on molecular testing results, highly symptomatic patient, I’ve definitely started with chemotherapy at times and then switch over to IO when it’s a little bit more of a controlled situation. I think that’s a reasonable thing to do.

DR LOVE: Same thing they do in lung.

DR MESSERSMITH: Yeah.

DR LOVE: Same exact thing, before they get the EGFR back or whatever. Okay. Keep going.

DR MESSERSMITH: So CheckMate 142, this was a study looking — is mostly in the second-line setting. There’s also Cohort 3 with the dual therapy in the first-line setting. But this looked nivo versus nivo/ipi and kind of set that — help us figure out what do we want to use, 1 drug or 2 drugs. You’re going to get some higher toxicity, obviously, as you use both.

And you can see that you have that higher response rate when you combine both drugs, and so you’ll see it differ from study to study, but when you add the dual checkpoint you’re going to get an extra 20 or so percentage points, 15, 20 percentage points on the response rate, but then you’re going to have higher toxicity. And it’s just food for thought in terms of trying to figure out whether to use 1 drug or 2, and that’s a conversation with patients. And it kind of gets back to the point you said earlier, Neil, where if I’m really convinced I’m going to need a response in order to prevent an issue, organ failure or something else going on with the patient, I might use a dual checkpoint approach. And if I have time in terms of growth kinetics and other things, then single agent would be reasonable as well.

And these are the overall survival curves just showing that in terms of survival both of those cohorts, Cohort 2, Cohort 3, do quite well either first or second line, the nivo and ipi.

From a safety standpoint, again as you look across Cohort 1, which is the monotherapy, versus the other 2 cohorts, which are dual therapy, you’re going to see higher treatment-related adverse events and immune-related adverse events, but for someone where you really banking on response it might be worth it, and it’s something to talk about.

The other thing, Neil, that surprised me is now that I’m asking everyone the percentage of people with squirrely potential autoimmune diseases in the past is higher than you think, where they say, “Oh yeah, I think I might have had Crohn’s a long time ago, or maybe it was something else.” And you’re trying to dig through their records and find it. So if I’m worried about kind of a squirrely autoimmune history I might go with a 1-drug combination rather than 2.

So turning now towards BRAF, this is the BEACON study, which really set the standard of care, looking at encorafenib, binimetinib, and cetuximab. And at the end of the day the encorafenib and cetuximab won out. This looked at response and overall survival, and this was presented by my good friend Scott Kopetz from MD Anderson.

So looking at the fact that the doublet and triplet had very similar efficacy with basically lower toxicity there really wasn’t much point in having that third drug. And so if you look at the hazard ratio it was 0.61 compared to control. Unfortunately you don’t really see a flattening of the curve. There are so many different resistance mechanisms that can occur here, and unfortunately patients do tend to progress over time.

And Scott also presented the quality-of-life data just showing that there was better time to definitive deterioration, so that was prolonged if patients were in the targeted therapy arm. And also the patient global impression of change also improved with the targeted therapy compared to the control group, indicating that you’re not sacrificing quality of life.

The BREAKWATER study is targeting BRAF-mutated colorectal cancer in the first-line setting, looking at encorafenib and cetuximab, and then there’s a combination arm with chemotherapy. So the initial safety lead-in was just to make sure that the combination with chemotherapy was well tolerated, which it appeared to be the initial encorafenib/cetuximab first or second line — efficacy data indicated that there does seem to be a promising response rate, especially in the first-line setting you can see the CR and PR rates are close to 70%.

And then looking, again, at progression-free survival of the various arms, first line and second line, first line across the top, second line across the bottom, these were small numbers, but it seemed to combine pretty well with either FOLFOX or FOLFIRI. And as expected, your first-line curves are going to look a little bit better than your second-line curves.

So Scott actually made this slide, which I think is a really nice slide, looking at BRAF-mutated colorectal cancer in terms of what’s coming. There’s an adjuvant trial that’s in the pipeline. First we have BREAKWATER and SEAMARK, I’ll show you a slide on SEAMARK in a minute, it’s kind of an interesting study. BEACON, of course, is done, and there’s multiple studies in the refractory setting going after this patient population.

So SEAMARK I thought was kind of an interesting study, and it’s looking at whether or not we should be adding the BRAF targeting approach to immunotherapy. This is in BRAF-mutated MSI-high patients, and what’s interesting is the targeted therapy, your encorafenib and cetuximab, may also have immune modulating effects in addition to the targeted effects. So I think it’ll be very interesting to see how that trial reports out because the MAP-kinase pathway has been shown to be important in immune regulation, and we’ve seen multiple settings where a checkpoint inhibitor and a targeted kinase inhibitor — tyrosine kinase inhibitor seem to combine really nicely.

This is a study in SWOG. We have this open, as do multiple others, looking at encorafenib/cetuximab plus or minus nivolumab. There’s a lot of data showing that these BRAF tumors seem to be inflamed, and so adding early on the nivolumab — and this is for MSS. So unlike the SEAMARK study it’s proficient MMR, microsatellite stable. So those 2 trials I think will be a nice mirror image of each other to see how that goes.

And you can see there’s a 2:1 randomization with 75 participants. And Van Morris, also at MD Anderson, is the PI of that study.

Turning now to HER2 colorectal cancer. So John Strickler from Duke presented this data looking at the MOUNTAINEER study. And what’s kind of cool about this study is it started out as an investigator-initiated study and then got converted into an industry-sponsored study, kind of fast tracked, so that’s always nice for investigators to see their initially small, single-center investigator trial go up to a nice big trial to show the proof that it seems to be working pretty well.

So this looked at tucatinib/trastuzumab versus tucatinib alone. And you can see there the efficacy endpoint was overall response. And here you see the combination arm, tucatinib and trastuzumab, 38% response rate, which is actually a pretty impressive response, with a median duration of response per blinded independent central review of 12 months.

And here’s a waterfall plot looking at the combination. Again, the tucatinib is your small molecule. It’s blocking the signaling. Trastuzumab is your large molecule, monoclonal antibody. And you can see that there’s a number of CRs and PRs and about 65% of the patients had at least some type of tumor reduction.

These are the PFS and OS curves. Again, we don’t quite get a flattening here, but nonetheless good efficacy and a good option for patients in this setting with tucatinib and trastuzumab. On the other hand, tucatinib alone did not seem to work. It kind of reminds me of the MEK inhibitor and BRAF inhibitor story, and BRAF. Tucatinib alone did not seem to work, and it’s been shown by Scott and multiple others that there’s a number of feedback mechanisms where you kind of need that monoclonal antibody at the top of the signaling, if you will, to prevent some of the feedback mechanisms from just going right around your drug.

So looking at the treatment emergent adverse events greater than 10%, and I think most of these I think we’re all pretty familiar with, with any of the tyrosine kinase inhibitors. You’ve got your GI, some diarrhea and nausea, some fatigue, rash, et cetera. So it seemed to overall be fairly well tolerated. You can see the incidence of Grade 3 or higher was pretty low. You obviously need to keep an eye on the hypertension.

So the following study is MOUNTAINEER-03. This is a global Phase III trial, and this is going to be in the first-line setting looking at tucatinib/trastuzumab and FOLFOX versus FOLFOX with one of the other targeted therapies, but the primary endpoint being progression-free survival and secondary being overall survival and response. So we’re looking forward to that trial getting completed.

G12C mutations, so adagrasib. This was a New England Journal paper Rona Yaeger looking at this G12C inhibitor with or without cetuximab. And this is a drug that irreversibly and selectively binds to KRAS G12C in its inactive state, and it’s highly potent and highly selective.

So this is actually fairly rare. It’s hard to find these patients. We’ve been looking and only really had a handful over the last few years. But you can see that you get a nice set of partial responses in the monotherapy arm. You look at the progression-free survival curve in the upper right, and it’s not long-lasting. You see it’s down to 15% at the 12-month mark. Fairly good survival with close to 70% survival at the 12-month mark. But nonetheless we’re not getting that kind of flattening that we like to see with immune therapy.

When you combine them your response rate goes up. Here you can see almost more than half the patients are getting a partial response or at least stable disease, and you’re going up on your 12-month progression-free survival to 24%, with an overall survival 61% at 12 months.

And so this is your summary here just showing that the partial response rate went from 19 to 46% when you have the cetuximab in there, and fairly decent stable disease. You can see the number of progressors was actually zero in the combination arm, so at least stability if not response when you’re able to pick these folks up and get them on these studies.

Returning now to another G12C inhibitor. This is sotorasib. This was the CODEBREAK study just looking at sotorasib and panitumumab, so basically a similar subset of patients. This was second line and beyond, and again showing a fairly nice percentage of tumor responses. And they say here there was a reduction in target lesions in 88%, so not a lot of progressors, which is always nice to see.

And then in the swim lanes to the right you can see the kinetics of response and progression and also many of the patients still have ongoing treatment.

These are changes in target lesions over time. And again, not quite like immune therapy where they kind of flattened, but you do see some nice flattening, and then you start to see some of these tumors escape, and you see that the — some of them start to progress over time. But overall pretty good control, at least for the first 6 months on the study.

Treatment-related adverse events. Again, I think pretty similar to what we’ve seen with other agents. You get some rash, dry skin, pruritus, nausea, that type of thing. And fortunately fairly rare on the Grade 3 side effects. You do have to keep an eye on magnesium levels with this drug class.

And that’s it. Thank you so much.

Other Therapeutic Considerations in CRC — Pashtoon M Kasi, MD, MS

DR KASI: Hi, my name is Pashtoon Kasi. I’m the Director for Colon Cancer Research at Weill Cornell. I also focus on liquid biopsies here at our cancer center. What I wanted to talk and discuss today was about other therapeutic considerations of colorectal cancer in terms of data and papers that have been developed in the last year or so that are going to be relevant and may already be changing clinical practice. Our email and contact is noted as on the slide.

The first topic or the first set of papers that I wanted to focus on which would set the theme for the remainder of several articles of interest that are changing clinical care is this whole area of so-called liquid biopsies or in the clinic right now, this refers to circulating tumor DNA or ctDNA-based testing. At ASCO in 2022, there was a whole session that was dedicated for the first time focusing just on ctDNA, and as shown here in the slide, that was deemed as a dawn of a new era which in many ways for solids in general. But then colorectal cancer in specific is something that is already changing practice and how clinical trials are being done.

One key publication that we are a part of that we wanted to highlight specific to colorectal cancer which has been the poster child when it comes to liquid biopsies or ctDNA for the rest of the targets. We talked about liquid biopsies. This is what it’s going to refer to. It’s this publication in JCO which highlights all the different applications of liquid biopsies as opposed to the earlier liquid biopsies that were for Stage IV metastatic cancer patients or when the cancer was progressing to pick up acquired mechanisms of resistance. This is something that has moved up the journey or the ladder of a patient with cancer to minimal residual disease, molecular residual disease, MRD, a term that we borrowed from our hematology colleagues, to early screening and detection. And I’ll highlight some of the key trials and some of the key publications that are using some of these assays to corroborate the differences and also how it’s being used in clinic.

Broadly speaking, it’s important for the audience to know that there are different types of liquid biopsies, even within molecular residual disease and minimal residual disease. There are so-called tumor informed assays where a piece of tumor is sent to make a barcode simplistically of the patient’s tumor and you look for the same barcode in blood as opposed to plasma only or tumor uninformed assays. As the term suggests in the latter, you don’t need to send a piece of tissue or tumor. And to increase the sensitivity of these assays, there are other markers in the bucket of epigenomics or methylation that are done to increase the sensitivity of these assays. And these are very relevant for colorectal cancer which is the theme of the discussion today. Again, some key articles highlighting how this might be of value in the clinic as well as in clinical trials.

So setting the theme on broadly what has been one of the biggest advances in clinical care, as I said, liquid biopsies and ctDNA. The first publication is with our colleague, Dr Cohen, which was presented at ESMO. It looked at the outcomes based on ctDNA positivity and looking at the clinical outcome of the cancer coming back in terms of recurrence free survival. In this particular real-world analysis of hundreds of patients, they were looking at a tumor informed assay. And shown here are how patients did if their liquid biopsy was positive versus negative. You’ll see a common theme across multiple publications and presentations that we will highlight that the negative is not 100% that depending on how much time goes by from the time of the last assay, the recurrence free is plateauing off. But 80, 90% of these patients still remain cancer free. However, if you were ctDNA positive, and especially if you don’t do anything about it, you’ll see a consistent theme of the curves meeting the x axis where pretty much within a couple of years, you see recurrence of the colorectal cancer. And this is applicable to other cancers too. And you see a broad separation of Kaplan Meier curves, high hazard ratios. That’ll be a consistent theme as noted in this publication.

And the field is not yet ready for de-escalation, meaning that if somebody is ctDNA negative and they need chemotherapy based on pathology and risk features, it’s not like we’re not going to give them chemo, but it’s provocative based on this real-world dataset that the benefit was minimal in the folks who were ctDNA negative. Again, not something ready for prime time, but it kind of sets the theme for clinical trials.

Key takeaways that I had for this was that it does show that it is feasible, something that you can do. Not surprisingly, Stage III minimal residual disease or MRD rates were like 30% as opposed to 10% for Stage II. This is what we see in general, so it kind of corroborates clinical practice. And one area where I think, at least from my standpoint and I would say the community is still discussing this, but a lot of experts would agree that if you truly have a low-risk Stage II colorectal cancer patient and you weren’t planning on giving chemo and the result comes back positive, this is not a prognostic or predictive risk factor. This more so reflects persistence of disease. That person is not cured. So it may help improving outcomes by identifying patients who actually may need chemo despite what the risk factors say. And then finally, it goes without saying, it sets the stage for ongoing clinical trials that are using some of these assays. This data supports the rationale for enrolling in these trials.

Again, building upon the same theme, the next topic that — or the next publication is from the group in Japan, from Dr Kotani and colleagues. This was a landmark publication in Nature Medicine just published a few months ago. I would say in a really informed discussion with the patient in the clinic or any talk about ctDNA in colorectal cancer, I pull up this paper all the time to help answer some of the questions that patients and informed caregivers and colleagues may be asking us which is a great thing. And, again, you’ll see similar trends and themes. ctDNA positive patients do not do well. Patients whose ctDNA turns negative, they do well. And regardless of how you put them in risk phase and stages, the outcomes are better if you did chemotherapy if you were ctDNA positive. So it’s becoming more of a predictive marker as well. And not surprisingly, and maybe the assays will get — keep getting better, maybe there will be a time where we would forego chemo in somebody who is ctDNA negative because you can see the benefit of chemo in that subset is small.

However, this is not yet ready from a de-escalation standpoint but, again, highlights that you can use this in trials and it’s an integral marker, not just an exploratory marker. And one nice finding about this trial that I — that often came up a few years ago was being ctDNA positive was not necessarily like a black and white death sentence. It's something that’s dynamic. You can change the positivity to negativity as shown here in this light blue curve. These were patients who were ctDNA positive who turned negative on the adjuvant mop-up chemo and their risk was as good as somebody who was negative to begin with. Not surprisingly, somebody who was positive or turned positive during adjuvant chemo and the subsequent testing, these patients did not do well. This was an analysis on over 1,000 patients in a real-world setting using a tumor informed assay. And, again, brings up not only the feasibility, but the question of it’s not just one of the best prognostic markers right now, but it’s a predictive marker and more so reflects persistence of disease and also would help identifying patients who are at high-risk for recurrence and maybe who would benefit from adjuvant chemotherapy. More to come and I will, again, put a plug for enrolling in some of the ongoing trials that are open in numerous places across the country through Alliance and many of these other cooperative groups.

Often, the discussion puts a good segue into this landmark publication. Again, this was in New England Journal. This was an oral presentation at ASCO from Dr Tie and our colleagues in Australia. Until this presentation came out and this publication the same day in the New England Journal, there was always that question that all the areas that we talked about so far, these retrospective studies, registries, real-world, it’s not a randomized trial. Well now, you have a randomized trial. This is an effort from the group in Australia looking at Stage II colon cancer patients. And they did a randomized trial in which half the patients got the standard management and the other one got ct-guided — DNA-guided management. And as shown in this Kaplan-Meier curve, it achieved similar outcomes, meaning that you did not compromise the progression free survival, recurrence free survival in patients who got chemo based on the results of the ctDNA testing as opposed to clinical judgement or clinical care.

I think the study probably needs more attention and probably should have gotten more impact, but I wanted to kind of highlight how this compares to the data we had in the past. It’s important to remind ourselves that people whose ctDNA results are positive, that specific Kaplan Meier curve goes down to 0% after a few years, meaning that pretty much everybody virtually recurs if you don’t do something about it. So we’re comparing the results between ctDNA positive and ctDNA negative. And maybe that difference doesn’t seem big, but if you compare it to all the historic studies where ctDNA positive patients did not get chemotherapy, that number that’s at 86% several years out is a 0. So this is a huge improvement and shows that it is something that you can predictive act upon.

DR LOVE: So you kind of very cautiously positioned this as something that should be considered in terms of clinical trial participation, but I’m seeing people doing it, investigators and docs in practice, all the time. They’re getting it paid for and they’re using it. Are you not using it outside of trial yourself?

DR KASI: So yes and no. So like this particular situation, for example, a Stage II patient where you weren’t planning on giving chemo and the results come back positive, I think the positive result is easy to act on. And as shown here in this next slide as well, there are several landmark registries and big publications where if you don’t act on a ctDNA positive result, it doesn’t matter if it was Stage I, Stage II, Stage III, virtually all those patients have recurrence. The publication by Dr Tie et al shows that that bar is, as you can see in this arrow, is cancer free, a good 86+%. So people don’t realize that this is something that’s truly a great finding. And I remember asking the question to Dr Tie as one of the discussants at the meeting at ASCO that if you had a patient tomorrow with Stage II colon cancer, would you use ctDNA? And her answer was yes. And I do agree on that approach.

For the Stage III, I think the key finding where I think the field is right now to understand is what a negative result means. Because a negative result, I caution patients before even the results come back that a negative result means 2 things. One is best-case scenario, you’re cured. Or the second possibility is that we’re looking for a needle in the haystack and maybe the best of tests didn’t find that needle. Or in the immediate postoperative phase, there’s a bigger haystack from the background noise of healing. So we just have to be cautious about not overinterpreting a negative result, equating that to cure, equating that to getting no chemo. If the plan is to give chemo, especially in a Stage III or a higher Stage II, you can use it for monitoring, surveillance. There’s data about it picking up cancer months before the scan picks it up. So yes, we are using it in the clinic, but with the cautious interpretation of what negative results mean.

And I would say we’re lucky to have many trials, both of Stage II, Stage III. And I think right now with some of these trials running through many cooperative groups, I would say in the United States, we do have a trial to offer as part of our clinical care by using these routine assays.

DR LOVE: All right. Please continue.

DR KASI: Again, to highlight the key conclusion from Dr Tie et al, they reduced adjuvant chemotherapy. So the number of individuals who got chemotherapy in the ctDNA arm was half as many as opposed to the clinical judgement. So you got and achieved a similar recurrence free survival with only half as many getting chemo. And chemotherapy comes with its own baggage, neuropathy, other issues, if somebody does not need chemo. The first statement actually in the NCCN guidelines for Stage II is a frank discussion about the low benefit or the low-risk of recurrence because the most important thing to cure them is surgery which has been done. So there is concern that we are overtreating. And the trials right now, the CIRCULATE-US, which is actively enrolling, this is important to highlight that it at least justifies if you still had reservations about using ctDNA in the clinic. With all this data, you should at least not have reservations about putting those patients on ctDNA-directed trials where decisions are being made in a controlled fashion under a trial setting.

And then, again to your earlier question, in the real-world utility while I think there is still some debate, I would say I’ve heard more experts agree that if you weren’t planning on giving somebody with Stage II colon cancer and their assay is positive, this is not a prognostic indicator. This means that it’s persistence of disease. You should act on it. And the data from Dr Tie et al supports that you can change the recurrence free survival from 0% in a few years to almost 86% disease free.

The next publication is more of a consensus statement that was published in JCO from the colorectal cancer expert panel. And I’m just going to highlight the key summaries. But they tried to look at 7 key practice questions and come to a consensus to help day-to-day questions that come up every week on tumor board, on a patient that is in front of you. So what were these questions?

So the first question they asked was the utility of doublet versus triplet chemo, FOLFOX versus FOLFOXIRI, modified FOLFIRINOX in patients with unresectable colorectal cancer. And in short, the answer here is depending on the individual patient, you can use triplet, you can use doublet. I would say triplets are coming back in fashion. And also, the doses that we’re using of the irinotecan and the 5-FU with modified FOLFIRINOX or FOLFOXIRI are not the same as they used to be. So patients are able to tolerate it. And where possible, there is data suggesting that there is probably an overall survival benefit, better response rate with the utility of triplet. So in the right patient, I would use a triplet. And this is what the consensus statement also said.

It goes without saying, in the mismatch repair deficient MSI-high colorectal cancer which is about 4 to 5% in the metastatic setting, immunotherapy in the form of pembrolizumab is FDA approved. There was also a question regarding the utility of that in just MSS TMB-high. I think that’s where the TMB more than 10 is not as good of a cut-off for patients with GI malignancies as well as colorectal cancer. So caution there, unless it’s a crazy high, hypermutated, polymutated MSS colorectal cancer, we see a few a year, these are present. So outside of that indication, immunotherapy, it’s wise to not use it unless it’s in the context of a clinical trial where the patient might be getting something else in addition to a PD-1 blockade.

The third and the next few questions were around the RAS/RAF wild type colorectal cancer. And I would say last year, 2022, was kind of the year for the advances and more research on this particular subset with the advances for colorectal cancer coming in subsets. This particular subset, we learned more about. And for the truly left-sided RAS/RAF wild type, and we have some landmark publications highlighted as well in the talk later, anti-EGFR use alongside chemotherapy whether it’s panitumumab, cetuximab, is recommended and should be used, not for the right-sided in the first-line, but definitely for the left-sided.

We saw approval in the utility of encorafenib with anti-EGFR, cetuximab, panitumumab, through the BEACON study that was published a few years ago. It’s now something that’s available second-line and beyond for patients with BRAF V600E mutant colorectal cancer. So one chemo-free option in the second-line or beyond that’s available. It goes without saying that every single patient with metastatic colorectal cancer should get comprehensive panel-based next generation sequencing based testing at diagnosis so you know who are these subsets who are MSI-high, who are these subsets that are BRAF mutant, who are these subsets that are RAS/RAF wild type so you could be more precision medicine-based approach for these subset of patients.

For the ones with peritoneal metastases, the PRODIGE study looking at the benefit of cytoreductive surgery with or without HIPEC. While HIPEC didn’t offer additional survival benefit, cytoreductive surgery led to a median overall survival of upwards of 40+ months. So in the folks who have peritoneal only metastases, this is something that’s recommended.

For the ones where you can’t resect liver metastases, the guideline also looked at the question of can you use SBRT and this — or the selective internal radiation therapy or Y-90 or embolization. This was recommended for the ones who are unresectable more so favorable opinions regarding SBRT. For the SIRT or Y-90, the statement — or the consensus was more so that it’s not recommended for everybody. Again, there’s no such thing as not for anybody. So in the right context, it shouldn’t be just routinely done, some caution was advised because of the collateral damage that you can have from these therapies.

And then for the ones who are oligo, from the Greek word few, metastatic liver metastases, you could do perioperative chemo, you could take them for surgery alone. Again, these were things that were discussed in more detail. I just wanted to highlight and summarize the 7 key takeaways or questions that are — that come up often that are available in this consensus guideline statement.

DR LOVE: Going back to that first one, doublet versus triplet. I’ve heard that discussed as it relates to BRAF patients, but what other situations do you think about triplets?

DR KASI: I would say the right-sided tumors that in general you don’t have the option of adding EGFR. There is a rise of colorectal cancer in young individuals. Individuals in their 20’s, 30’s and 40 are getting diagnosed with colorectal cancer. Often because — they get diagnosed because it’s symptomatic, it’s often metastatic at the time of presentation. The question of conversion therapy often comes up. Somebody is not resectable today, but if I can convert them or shrink by X% or if I can shave off the tumor from the blood vessel that my surgeon could do surgery for. I would say in summary, there are a lot more situations. Obviously, it goes without saying, it has to be somebody with a good performance status and preserved organ function. But it is not the traditional FOLFIRINOX dosing with the bolus 5-FU and the irinotecan at 180 mg/m2. When we are using these modified regimens with no bolus and the 5-FU infusion at 2,400 in the US population, the irinotecan capped at 150 and now there’s also suggestion about using pharmacogenomics for DPYD and using T1-A1 base dosing. These are tolerable and doable and feasible regimens that I would say are being used more often than they were a few years ago.

DR LOVE: Please continue.

DR KASI: So going back to the segue of the anti-EGFR or the subset who are RAS/RAF wild type. Over the years, this has been a story of precision medicine and evolution. We knew that, from almost 10 years ago, that somebody who had a KRAS mutation maybe they didn’t derive benefit. Then, we found out maybe the BRAF patients also don’t derive benefit. Then, the whole sidedness question came up. So we’ve gotten better at selecting patients for anti-EGFR in the first-line. And we have all these exploratory retrospective analyses that show that there is probably a survival benefit. And some studies, I’ll show you some data, it’s upwards of almost a year. But every single time this question comes up, it’s still a debate question. I personally don’t think it’s a debate question anymore. But it’s still a question, do I use anti-EGFR or anti-VEGF first-line? Well now, you have a randomized control trial, the so-called PARADIGM study, where they showed in a randomized trial fashion, this was plenary at ASCO. You can see the hazard ratio. You can see the OS difference between the left-sided RAS/RAF wild type tissue patients who got anti-EGFR with doublet chemo versus anti-VEGF that this for the first time showed that it’s not just the response rate which is higher, as you can see, an almost 15% difference there, but more so this leads to a better overall survival. Some of that could also be because you can see you have a better response rate, maybe you’ll have a better shrinkage of tumor and cancer that leads to the benefit. Regardless, I think this kind of set the stage for this being as a first-line preferred option. And there’s an uptake of this more so in the community now that this got presented.

And my conclusion or takeaway here is I’ve summarized here in this table an NCDB analysis, the landmark CALGB 80405 study, the PEAK study, the FIRE-3 study and the PARADIGM study. If you truly look at the subset that should get an anti-EGFR which is your left-sided, your RAS, your BRAF wild type and I’ll throw in HER2 there as well, then this is OS. At the end of the day, we were looking for overall survival. It’s not just a meager few months. You can clearly see a consistent pattern and trend. And sometimes in the first-line setting, you may or may not have the results of the tissue sequencing back. There’s a potential utility for liquid biopsies as well. It’s now in the NCCN guidelines that you could use it for the rapid turnaround. As quickly as within 6, 7 days, you already know who is your MSS, RAS/RAF wild type patient who you could use anti-EGFR in. And that could equate to the better overall survival shown now in a randomized trial fashion and backed up by multiple analyses as shown here in this table.

I also wanted to highlight this other publication that kind of builds upon this further. And also, I’ll highlight why liquid biopsies might be important. So this is the same study, the PARADIGM study. This was presented at ASCO. And then 6 months later at ASCO GI, the same group looked at liquid biopsy ctDNA analysis of the same subset of patients who got the anti-EGFR and anti-VEGF that I showed you on the previous slide. And what’s intriguing is you can see a bunch of KRAS mutant, BRAF mutant as well as other mutations in the MAP kinase pathway that are resistance mechanisms and people that you may not consider giving anti-EGFR to were in the treatment population.

Now what happens if you further hyper-select these patients, that’s what they called it in their paper, and then look at the data? So in the hyper-selected patients, again, I wouldn’t necessarily call it hyper-selection because these are patients who shouldn’t be getting anti-EGFR anyway in our hands. But what happened if you did that? That benefit of 34 to 37 months goes up to 42 to 36 months. Again, going back to summarizing the previous data, look at the numbers. If you just select the right patient for anti-EGFR therapy, that survival number starts going upwards of 40+ months consistently across studies and then, you know, is in the low-30’s for the ones who are not selected. So some people question the rash part. Well if you’re not going to use anti-EGFR in the first-line, you’re going to use it in the second-line. So the fact that you won’t get the rash first-line if it, you know, you have to have a frank discussion with the patient why you are not going to consider anti-EGFR, in my opinion, when you have a 7-month+ OS difference. And in the real-world, that difference is even higher. And, again, reiterating the lower left liquid biopsies as shown here in the analysis done by the Japanese colleagues.

And then building upon the story even further on the anti-EGFR part, the group from GONO looked at the question of, you know, do you really need the triplet chemo if you are using anti-EGFR as your backbone? If the anti-EGFR is the key in the therapy selection, maybe you could spare the extra toxicity of the extra chemo. And that’s exactly what this presentation at ASCO, and now it’s in the JCO as well, the full paper. And they did not find a difference between doublet versus triplet chemo in the folks who were getting anti-EGFR. So it actually, again, builds upon the anti-EGFR selection even more that you could achieve the same outcomes with less chemo and you could reserve the other chemo for later line use. And that also might be the reason why you could get better overall survival because you’ll have more options. So in terms of choosing which patients for triplet, you could potentially spare the triplet toxicity of chemo in the ones who you are choosing an anti-EGFR as a biologic. So this was a good takeaway from this particular study where you can consider doublet as your backbone if you are choosing anti-EGFR as your regimen. If the patient is not a candidate for anti-EGFR because of KRAS mutation, BRAF mutation, maybe in those scenarios if you’re using anti-VEGF, if they have a good performance status, maybe you could use triplet in that scenario. So it’s further refining the first-line choices with all the data that came out in 2022.

And then in the subsequent line therapy, if you’re using anti-EGFR in the first-line or later-line, we know from elegant work done by many European colleagues and also colleagues at MD Anderson looking at some of the half-life of these clones, these resistance mechanisms that develop to anti-EGFR, well you could potentially lose them over time. So the tumors are not completely resistant or permanently resistant to a targeted therapy. Three trials that all serendipitously start with a C, the CAVE, the CRICKET, and the CHRONOS, they looked at this question of rechallenge which is an option for somebody who might have had initial response and then later progression. And, again, this is one more real-world utility of an NGS-based ctDNA assay or an assay that at least looks at all the mutations in the MAP kinase pathway. The key takeaway is that if you were liquid mutant, that if you had resistant clones in your liquid biopsy, you derive pretty much the minimal versus zero benefit. All you’re getting is the rash from EGFR, probably no benefit. But if you were liquid wild type, so not tissue RAS/RAF wild type, but liquid wild type as well at the time of your EGFR rechallenge, and you can use it in the real-world because you can get the results back within 6 or 7 days, then you can spare the toxicity to those who don’t need it. And the outcome of CAVE and CRICKET studies, this publication looked at pool data analysis. You’re achieving a PFS of over 4 months and an OS benefit in refractory later-line setting of upwards of 17 months. And the CHRONOS study went one step even further. They did not even include patients who were liquid mutant. They clearly believe that those patients should be spared the toxicity. It’d probably be unethical to give them anti-EGFR therapy if you clearly know that they have resistant clones. And shown here in this waterfall plot, as you can see, the response rate and the benefit in the ones who were anti-EGFR candidates. And shown here in this illustration is simplistically what happens to a patient’s tumor on targeted therapy, that you get a response then over a period of time, you lose the response because there are probably new resistant clones or a resistant clone that was already there, but then has the ability to propagate. If you do a nontargeted therapy holiday, you can potentially allow for resensitization for “EGFR rechallenge or recycling or resensitization” of the same targeted therapy which I would say is also something that can be done in the real-world setting.

As the authors of this particular publication called it, zero mutations ctDNA triage, meaning that before you consider a person for anti-EGFR therapy, just do a liquid biopsy to make sure they don’t have any mutations that would make anti-EGFR a failed exercise. You could argue, well the benefit is not tremendous. You can at least spare the toxicity to the patients who don’t need it.

Moving on, in the “salvage” or refractory line or beyond the traditional FOLFOX, FOLFIRI, FOLFOXIRI with the traditional biologics, what are the options and what are we learning about the drugs that are available in that setting? We have regorafenib and then we also have the antimetabolite, TAS-102 or FTD, available. What are we learning about these drugs? This particular ESMO presentation builds on the ReDOS study from Dr Saab and colleagues looking at the dosing of TKI. It’s one thing that we are consistently learning that less is more. So instead of the traditional 180 mg — 160 mg dosing of regorafenib, they started at the 80 mg dose and also preemptive clobetasol use. The hand-foot syndrome is something that we see with TKIs. Rather than reactive prescribing later when it’s worse, starting off with preemptive prescription for that. This was a network meta-analysis which showed that compared to best supportive care or the higher dose of the TKI or some of the other drugs and trials with fruquintinib, which is an anti-VEGF that we’ll talk about later, that the benefit, as you can see, was almost an OS of 9.8 month.

And going back to the original ReDOS study shown here in this illustration, more patients were able to stay on the therapy and didn’t have to come off for toxicity if you did an 80 mg starting dose with weekly escalation and preemptive versus reactive treatment for the clobetasol. And if your patient can tolerate treatment better, their quality of life is better and they’re going to stay on the drug better. And that downstream leads to a better progression free survival and overall survival. The outcomes of patients with colorectal cancer has been a continuum of care. It hasn’t been one wonder drug. It’s just the fact that we have all these options, one after the other after the other, that can be used and reused that has allowed for the survival to go up from a few months a decade ago to upwards of several years now. So it’s important to recognize and know about all these options at the right time.

And then along the same lines in the salvage and refractory setting, this randomized control trial that was published in — that was presented at ASCO GI is also a new standard of care, the so-called SUNLIGHT study, looked at the question of the addition of bevacizumab to the TAS-102 or the FTD/TPI antimetabolite that’s FDA approved already. This looked at the question of the addition of anti-VEGF which is the same question of bevacizumab beyond progression that we have been doing with traditional IV chemotherapy. This looked at the continued use of bevacizumab even in the later-line setting. This was a positive clinical trial. It met its endpoints. You can see the overall survival as well as the progression free survival were meaningful. Sometimes, our colleagues would argue that the PFS with some of these drugs is almost the next scan. Before you even get the next scan, somebody is progressing. But here, you can see that there is a meaningful improvement in that endpoint.

And what was also remarkable was that the benefit was preserved across subsets and across the patient population. Whether it was your patient who had bevacizumab in the past, whether it was your KRAS mutant, whether it was a patient with liver metastases, without liver metastases, the benefit was preserved across all subsets as shown here in this forest plot. It’s important, I think the idea that all these trials are now also looking at quality-of-life variables and global health status variables. And it’s nice it’s being reported at the same time rather than ad hoc analysis years later. Not surprisingly, this regimen also delayed the time to deterioration of the global health status. So it’s not just the tumor that slowed down, this was not coming at the cost of compromising the quality-of-life of the individual which is important as we talk about these patients being on therapy for years.

So the key conclusion or key takeaways I often kind of talked about are these tools in our toolbox for our patients with metastatic colorectal cancer. Now, we have the option of the addition of anti-VEGF to this antimetabolite that’s already FDA approved. I would say this is not new. This was already in the NCCN guidelines over a year ago when the initial Lancet Oncology publication came out. I think this randomized trial further brought this to the attention of the broader global community and kind of corroborated the already approved NCCN guideline recommendation that this is an option. I would say it’s important that this is not something that you would be doing or should be doing when you’re — I’ve heard this being brought up when hospice is pretty much the only option left. That’s not necessarily true. This is, in my opinion, a third-line option. Or if you were doing triplet chemotherapy upfront and maintenance, this is technically your second-line option post progression on maintenance as well. Rather that rechallenging oxaliplatin, more curating neuropathy, you could spare those options for later use. So this randomized trial makes it an option, this SUNLIGHT regimen, in second-line post progression or third-line compared to some of the other drugs preferentially in many books.

And building upon the data further, this real-world registry Phase IIIB study looked at almost 1,000 individuals who got the trifluridine/tipiracil, the TAS-102, the drug we just talked about with anti-VEGF. Here, they looked at other variables of what’s actually happening in the real-world. Sometimes, the real-world does not reflect the trial data. In this elegant analysis, I found it very interesting and intriguing that the longer you could stay on the drug, you were, of course, achieving ongoing control and better overall survival, but this was not necessarily coming at a cost of compromising quality-of-life. This was preserving it leading to efficacy without delayed, as you can see, patients without ECOG performance status deterioration. So most of the times, there are accumulated toxicities of certain drugs and regimens. The question of efficacy often is brought up with trifluridine/tipiracil. I often tell my patients that I would say at least safety is something that, and tolerability and quality-of-life, has been of a little concern and often, we’ve done earlier on as you can see here. It’s not something that patients are on for just a couple of cycles. Some patients can be on it for a long time. And we have to be careful. And we interpret some of these median progression survivals, overall survival, these are medians not averages. There are definitely patients who derive minimal benefit, but there are also patients who derive a long benefit for a long period of time without compromising their quality-of-life. And now with the addition of bevacizumab, this is even more pronounced.

One small practical observation that serendipitously, we had reported back in 2016 was the observation that if you do get neutropenia or low white cells, again, this is different from neutropenic fever, just the low white cells is more of nuisance. But it’s actually a good prognostic factor, both for progression free survival as well as overall survival. This was corroborated in the randomized trial as well as in this 1,000-patient registry. So it begs that question of rather than decreasing the dose or delaying it, it’s not unreasonable. I know the question of growth factor support sometimes in palliative setting is questioned. But if that is something that is a surrogate of good prognosis and maybe a predictive marker of how much drug gets into the system, maybe something to consider not as an adverse issue. We are not necessarily dosing to neutropenia as in some of the gyn-onc regimens. But rather than decreasing the dose, as long as you’re not having fever or other issues, this is something that you could work with the patient in terms of what is the best strategy to keep the dose intensity going.

And then the other randomized trial that hopefully would also be another option soon in the toolbox is this FRESCO-2 study which has built on the FRESCO-1 randomized trial looking at the oral VEGF agent called fruquintinib. This showed, again, met its endpoint. You can see the differences in the survival key endpoint that was achieved versus placebo versus best supportive care.

And the waterfall plots also show and the side effect profile is nothing that we’re not familiar with as GI oncologists. This is an anti-VEGF agent, so you’re dealing with the same issues as you would be with the previously approved anti-VEGF agents. Not surprisingly, with hypertension and some of the other side effects that are well-known and things that we are very familiar in how to manage them. The benefit is also preserved in previously patients exposed to anti-VEGF. Anti-VEGF is obviously focusing on the tumor microenvironment, so it’s not surprising with the data from the SUNLIGHT, with the data with bevacizumab beyond progression and now this continued benefit with an anti-VEGF agent that this is still providing benefit in our patients with metastatic colorectal cancer. Again, not necessarily a homerun, but I would say this is something that probably will get another approval as another agent and maybe has the convenience of being a pill as opposed to ongoing intravenous infusion which we also found that in the setting of pandemic can be very relevant in terms of the visits to the hospital or the so-called time toxicity, the time that patients spend in getting their treatments at all these cancer facilities.

So, again, I like to quote this slide which is from 2008 which, again, shows that the advances for patients with colorectal cancer were not just from one wonder drug, it was all the advances that were happening in parallel, both in terms of systemic therapy options, advanced surgery, allied specialties, all of them add up to the overall survival advantage with this option, as the authors quoted, potentially a new treatment option in refractory metastatic colorectal cancer.

DR LOVE: I was going to ask you do you see fruquintinib as a sort of, I don’t know, competitive but similar to or replacing regorafenib?

DR KASI: So it’s a similar question that even comes up even right now with regorafenib with TAS-102. I don’t necessarily see them as competitors. I see them as drugs that the sequencing question may come up. But the mechanism of action is still different compared to regorafenib. So I don’t think it will be taking its place, but the question, the unanswered question, would be would these 3 salvage regimens — there is a bias now towards using TAS-102 now that we have the data with bev. That PFS and OS is unmatched unless somebody is not a candidate for anti-VEGF for some reason. But we don’t know the correct answer yet, but I don’t think it will replace the drug. It will be one more option in the toolbox.

DR LOVE: And do you think it’s better tolerated than regorafenib? 

DR KASI: I would say we’ll have to see the real-world experience. In the trial setting, the side effects that they’re reporting as shown here in this table are very similar to what I would expect with any of the anti-VEGF agents. There were no unexpected adverse events that we weren’t familiar with. As you can see, most of them were minor grade AEs with hypertension being the most prominent one in one-third, fatigue. But nothing that we are not used to. And the Grade 3+ events were only seen in about 10, 13% with hypertension. All the other severe AEs were less than 5%, so nothing that we’re not familiar with in terms of managing. So I think I don’t expect that toxicity part to be an issue here with this particular drug.

DR LOVE: Okay, please continue.

DR KASI: And then, you know, advances have been coming in these molecular subsets. We talked about the RAS/RAF wild type, we talked about the BRAF mutant, we talked about the MSI-high. One interesting observation that is now backed up with several other studies. This one particular study of note being one of the first ones looked at the question of benefit of immunotherapy-based regimens in patients with microsatellite-stable mismatch repair proficient colorectal cancer. As a reminder, the immunotherapy, while it’s standard of care, it’s the only situation where I’ve heard the word cure being used with MSI-high colorectal cancer even in Stage IV settings. These patients, when they do respond, it’s a gift that keeps giving. This is in sharp contrast to patients who are mismatch repair proficient colorectal cancer and microsatellite-stable colorectal where pretty much the responses are 0%. And patients should not be getting immunotherapy if they are mismatch repair proficient or MSS. And here, you’re seeing an overall response rate of 42% and a waterfall plot that looks pretty decent. But what was really intriguing or more intriguing was the observation that this is mainly being achieved in the subset of patients who do not have active liver metastases at the time. Shown here in the light blue are patients who had active liver metastases. Pretty much, as you can see, every single patient had progression.

Now it’s not like you can’t have had liver metastases. Just at the time of the study, either they had to be resected or ablated. And there’s another study that’s ongoing right now that’s allowing patients with no issue of liver metastases or if you had resected or ablated metastases without recurrence for over 6 months, this so-called BOT/BAL regimen. The BOT is the botensilimab, which is a novel CTLA-4 drug that I’ll show you the picture and more details in the next slide. And the other, the BAL, is the balstilimab, which is an anti-PD-1 just like any other anti-PD-1 that’s out there. This was presented by Dr El-Khoueiry and colleagues at ESMO World GI and there was some more update at ASCO GI.

And it is a new drug, this so-called BOT. According to the manufacturers, it’s an Fc-enhanced CTLA-4 inhibitor. It probably has more T-cell priming, more expansion, more memory. It also takes away the bad Tregs, probably decreased the complimentary toxicity. So maybe it’s a better drug. Maybe that’s what’s causing the response. Or is it the microenvironment of the lung-only or non-liver metastases patient? Is that driving the show here? We’ll know more. And there was also data just a few weeks ago by Dr Marwan Fakih and colleagues that looked at regorafenib with ipi/nivo, the so-called RIN regimen. And, again, overall, the results were disappointing in the microsatellite-stable colorectal cancer. And also the, a few years ago, the rego/nivo combination that was very fascinating in the Japanese cohort, but pretty much in the US cohort was very disappointing. The subset analysis of the patients who had lung-only metastases or non-liver metastases show similar patterns. So while not discounting this is a new drug, I do think the new drug is also building on the observation that patients with this subset of this setting where you have a non-liver metastases situation, it’s more conducive to possibly immune-based regimens.

So whether it’s the novelty of the drug or the lung-only metastases, it is the first time we’re seeing any activity of an immunotherapy-based regimen. So it’s very much of value and intriguing and heartening to see waterfall plots like this. Again, the work is not done or complete. But for the first time, we’re seeing a signal here. And like I said, there are right now ongoing clinical trials that are now selecting the patients with non-liver metastases for some of these regimens. I wish there were treatments and options that would be for all colorectal cancer patients. But I think this particular work highlights that there are some subsets where it’s more so molecular selection going on into selecting the right candidate for, let’s say, anti-EGFR therapy or the MSI-high for immune therapy. Here, I think it’s not uncommon. There is a frequent occurrence. Even today, I had a few patients who only have lung-only metastases who may benefit from such a strategy. Also, I think on the flip side, patients who, for example, have widespread liver metastases, they could be spared the unnecessary exposure to a regimen that may or may not work for them.

So in summary, I think the advances in the last year or 2 for colorectal cancer have taught us even more the value of identifying the subsets who may benefit more from a precision medicine-based approach, whether it’s the NGS-based testing, whether it’s the liquid biopsy, whether it’s the sidedness and more so now with this BOT/BAL regimen, the location of the metastases in the refractory line setting.

DR LOVE: I’m trying to even come up with any kind of hypothesis that would explain why it doesn’t respond in the liver and does in the lung? Anything that you can come up with or you’ve heard people come up with?

DR KASI: Yeah, there’s definitely a lot of work being done here. And actually, it’s not just colorectal cancer. We’ve seen this over the years with non-small cell lung cancer, melanoma. We understand that it’s not just the location, that the liver is the anatomic site of spread. The liver itself is an immunosuppressed environment. There is a lot of bad immune cells from a tumor standpoint in terms of high proportion of Tregs. There is a reason why cancers like going to the liver because they can then simplistically hide under the radar of the immune cell surveillance. So patients who have metastases to the liver often systemic therapy with immunotherapy hide under the radar. Our transplant colleagues knew about this from a while ago. From what I understand, the amount of immune suppression that’s required for a liver transplant is less than some of the other organs. There’s also some work published just a few months ago that argues that the liver might not just be a site of metastases, but simplistically it might be a command center, that there’s crosstalk going on between these metastases. So thinking out loud, could you do something different to the liver location whether it’s some form of surgery or radiation or we talked about the ASCO guideline statement recommending SBRT or Y-90 in the select cases where it’s not resectable? Could you view that as a separate battle that you could address separately and still allow for systemic therapy to be an option for the remainder of the body? I think it’s a question that’s being asked in some of these upcoming trials. And maybe that’s the new direction, understanding these as separate situations.