Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet the Professor, as today we talk about the management of colorectal cancer with Dr Chris Lieu from the University of Colorado Cancer Center in Aurora, Colorado.

We have a great faculty for this series. And later on, we’re going to show you the results of a survey we did of the faculty of the usual treatment practices.

As is always the case in our webinars, if you have any cases or questions you’d like us to discuss, just type them into the chatroom; we’ll talk about as many of these as we have time.

We put out a very brief 1-minute survey for you to take before and after the meeting. If you take that, you’ll get a lot more out of this and we’ll learn more about you.

We do webinars all the time. We’re doing one tomorrow, same time, same place, should be really interesting. We’re going to do a little update on PARP in ovarian cancer but really interesting, we’re going to really try to tackle the issue of Tumor Treating Fields with Dr Patel. I want to try to understand how this works, or even does it work.

Next week we’ll be continuing our Year in Review series with Drs Dorff and Sartor talking about prostate cancer. Just finished the GU symposium. A lot of great papers there and relevant to the next webinar on kidney and bladder cancer as well on March 2^nd with Professor Powles and Dr Milowsky.

We’ll be continuing our ER-positive, triple-negative breast cancer series with Dr Tolaney from Dana-Farber on March 7^th. And then we’ll be doing a really interesting program, it’s a fellow-up to the GI ASCO meeting, where we’re going to have 3 general medical oncologists on the webinar responding to a bunch of video that I’m going to gather from our faculty for the meetings that we did in San Francisco and see what they have to say about it.

We’ll continue this series. We’re actually doing 3 webinars as part of this colorectal series. And we’ll do Part 2 with Dr Strickler on March 22^nd.

Then we’ll be doing a program on ovarian cancer at the SGO meeting. We always go there every year. We’re doing 2 programs there, 1 will be on ovarian cancer, and the other endometrial cancer. Two gigantic papers about to be presented, first-line therapy of metastatic – guess what — chemo plus IO, supposedly positive studies. We’re going to see. Should be interesting.

A lot of you love to listen to our webinars. If you’re into audio programs, check out our Oncology Today podcast series, including a recent program with Dr Shroff, reviewing some recent presentations.

But today we’re here to talk to Dr Lieu about what’s going on in colorectal cancer. As always, we have a bunch of general medical oncologists in community-based practice. We just presented a whole bunch of their cases last week at the GU symposium, but they also gave me a bunch of colorectal cancer cases. So we’ll see what those are and what Dr Lieu has to say about it.

Here’s where we’re heading. We’re going to start out just chatting about one of Dr Lieu’s interests, and our interest as well. We always are curious about the issue of early-onset colorectal cancer. And then we’ll dive into our program with cases and papers and the survey that we did.

So Chris, great to work with you. We worked with your colleague, Wells Messersmith so many times. And I was just reflecting back. We did a program with Wells not too long ago on BRAF-mutant disease where he presented cases, and I edited it and then presented to Dr Kopetz. And when he started to do the presentation, he had the 3 cases up there, and I go, Wells, I just notices something, they’re all under the age of 40. And, of course, that really relates. And, in fact, the first case that you’re going to see is a 36-year-old woman who was totally fine, started to get some abdominal pain. Ended up with obstruction, in the ER. Thirty-six years old. Colon cancer.

You’ve got a bunch of really great papers that you’ve done in the literature. You’re doing this fascinating topic. I’ll just sort of flip through these just to get the audience interested in the topic and let you just chat in general about the work that’s going on in this field. What’s going on with the microbiome? I hear people talk, why are we seeing these early-onset cases? Any comment?

DR LIEU: Appreciate the opportunity to be here. And thank you for the invitation. And like you said, I think anybody listening to this certainly has seen this in their own clinic in regard to seeing how many young patients we’re seeing. And I remember seeing this trend, even when I was in fellowship at MD Anderson, and was just trying to figure out if colon cancer average age was 70, or if it was actually 30. Because I was just seeing so many young patients.

And when you look at the data, it’s pretty clear that since that the late 1980s or early 1990s, that there’s been basically a year over year increase. And even here in Colorado we took a look, and it looks like really since 2005, there’s been a 3% increase in our early-onset cases. Just every year, straight up until now. And we’re certainly seeing that reflected in our clinic.

When you think about, you want to know about this is happening. And I think that that’s a really complex question. And one of the things that you and I were discussing about was, we want to be able to just pick 1 bacteria, 1 environmental exposure, 1 risk factor that’s really leading to the increase that we’re seeing in our young adult population. But essentially what you’re seeing on this slide is that it’s probably a combination of numerous factors that are all working together that’s probably increasing everybody’s risk. But then, when you look at the individual level, it could be any number of factors that are from environmental to genetic to even the gut microbiome. And some of the things that we do to alter that, and that may even include antibiotics.

And then from a clinical standpoint, everybody also understands that this is a really tough population because they have different needs. So what happens when you get diagnosed with colorectal cancer and you have to undergo multimodality therapy, but you’re still in school. Or you have a young family. Or you’re just starting your career. And so, a lot of those factors are things that we really kind of focus on in some of the slides that you’re showing, and that just needs to be obviously, great multidisciplinary care, but care that also encompasses some of these other challenges that our young patients face.

DR LOVE: So I guess indicative of where oncology is today, we’re about to put out a 2.5 hour Think Tank on ALK in lung cancer. And your colleague, Ross Camidge, was — I saw a paper he did on fertility issues in these young patients with mutation-positive disease as we see with EGFR and ALK. What about fertility issues? Do these come up? We just did a whole program in breast cancer about fertility in breast cancer. Do you deal with this in these younger people?

DR LIEU: Absolutely! And it’s one of those things when we see young onset, or early-onset colorectal cancer, I think, honestly, a referral to Onco-Fertility is probably something that should happen unless a patient absolutely from the outset just declines it.

A good example of where this becomes a huge problem is in locally-advanced rectal cancer where we typically give radiation, especially for our female population. If you don’t transpose to ovary, you could essentially end their childbearing potential. And so, that’s something to consider, even individualizing the treatment that we give.

And I’ll give you one example of this. I had a very, very young 27-year-old, who came in with locally-advanced rectal cancer. Really wanted to avoid radiation exactly for that reason because even if you transpose to ovary, you can still deal with infertility issues. She was luckily enough to have an MSI-high tumor. And so, one of the things that eventually talked about was the idea that maybe we could try immune checkpoint inhibitor therapy, which is obviously not standard but we’ve seen great data in regard to rectal cancer and immunotherapy. We did immunotherapy. She had a complete clinical response. And we were able to again, preserve her fertility and actually even avoid a surgery.

DR LOVE: I always look for the things that come in the chatroom in the beginning because I know people have got things they want to ask and they put it right in the beginning. And as soon as we sat down, this came on from Hassan in the chatroom. Let me know what you think: 40-year-old lady, T4N0M0 left colon cancer with Lynch syndrome. Would you recommend adjuvant chemo? What about Signatera?

DR LIEU: Yeah. There’s a lot of data when it comes to Stage II colon cancer and the use of either 5FU alone, or combination chemotherapy. And when a tumor is MSI-high, we think that the recurrence risk is so low that we do not offer chemotherapy. In fact, for Stage II colon cancer that’s MSI-high, if you give them single-agent 5FU, the data shows actually detriment or harm in the group receiving chemotherapy.

I’ve actually dealt with this situation where the patient does have T4 tumor, and that’s the thing that makes me a little bit nervous. So I’m going to give you a very, very standard answer and to say, just because the risk of recurrence is so high with T4, I’ve traditionally offered those patients FOLFOX or CAPOX, even though they’re MSI-high and the risk is relatively lower. And the reason why is, just because of my concern regarding peritoneal spread with a T4 tumor.

Now, the answer that we really want to give is to utilize immunotherapy in this setting because we know — we assume how effective it will be. But the problem here, is that we really don’t have a lot of data. And in Stage III cancer, we do have the ATOMIC study, which has completed accrual — that was FOLFOX with atezo versus FOLFOX alone for MSI-high Stage III colon cancer. That will give us some idea of the impact of immunotherapy in the “curative” setting. But we don’t know that for Stage II yet.

So the answer is we’d certainly offer chemotherapy because of the risk of T4. In regard to immunotherapy, that’s the answer I truly want to give. We just don’t have any data in regard to that right now.

DR LOVE: So the chatroom is blowing up here. Like I said, we may never get to the slides if we keep going with all these cool questions. But I can’t resist them. Okay, so Dr Kumar who’s a doc with Florida Cancer Specialists, has a patient with Lynch syndrome. Status-post resection 3 years ago, now with an anastomotic relapse, but uncontrolled diabetes. Hemoglobin A1C is 10.5. The surgeon doesn’t want to operate right now. And the patient does not want a total colectomy anyhow, so they’re planning segmental resection. His question, kind of similar to what you were kind of alluding to, any role for temporary IO right now until surgery?

DR LIEU: Yeah. So, very, very interesting case and actually one that I had fairly recently. And I know we’re going to talk about ctDNA, but it actually relates to the case that I have that’s very, very similar to this. I had a patient with a pretty gnarly looking Stage II colon cancer that was MSI-high and was resected. This was not a T4 tumor though. And, given that we didn’t actually do adjuvant therapy because it was a low-risk, Stage II, MSI-high, we don’t give chemotherapy for those patients because typically, they’re going to do great. But the patient wanted a ctDNA test to look for the presence of minimal residual disease, so we sent that. And it was positive. And of course, did the usual CT scan. Nothing. And so we said, well, in the absence of disease, let’s just get a colonoscopy. It’s recommended in the surveillance period anyway. We got a colonoscopy and there it was, it was an anastomotic recurrence.

In that situation, the patient also, for similar reasons due to comorbidities, could not get surgery and we actually utilized immunotherapy. And that’s the recommendation honestly. I think whenever you have anastomotic recurrence, you can more or less say, it’s recurrence. You can call it Stage IV disease even though it’s not your traditional Stage IV disease, we utilize immunotherapy and the patient still remains disease free.

So that’s certainly my recommendation. And it’s probably the best and easiest thing that we can do in a patient with comorbid conditions where surgery is not an option.

DR LOVE: So I should have put on the agenda Part 1, chatroom. I’m going to skip the 32-year-old pregnant patient. Maybe we’ll get to that later, but maybe just to finish out this segment where we’re seeing all these questions about IOs and MSI, Swati wants to know, and everybody wants to know about neoadjuvant IO. I’m sure she’s referring to the Memorial rectal paper from The New England Journal, but also, just the general issue of even colon cancer, the possibility of neoadjuvant IO in MSI patients. Any thoughts?

DR LIEU: So there have been a couple of studies, obviously you had mentioned the dostarlimab study that had 14 out of 14 patients have a complete clinical response. That’s, obviously, phenomenal. Interestingly, for colon cancer, the Niche-2 – N-I-C-H-E-2 — study looked at nivo and ipi, very, very short course, prior to surgery and they had these remarkable response rates. Interestingly, they even had responses in microsatellite-stable colon cancer, which is somewhat unexpected. But when you look at the MSI-high group, I mean the complete clinical response rate was just tremendously high.

And then, MD Anderson has a cohort, Michael Overman has a cohort of patients that also showed, maybe not quite as good, around a 70% complete clinical response rate, but still, still, very, very high.

I think for rectal cancer, I think more and more people are actually doing this kind of “off label”, right, but just because the data has been so outstanding. I will tell you that there are large studies that are opening with dostarlimab, both in the rectal space and the colon space.

And so, there are trials that are open to try and answer some of these questions. But I think people, if you’re being honest, are seeing some of these patients that are offering neoadjuvant immunotherapy and the results, obviously thus far in the small studies, have been pretty outstanding. Very impressive.

DR LOVE: Yeah. Actually, I was mentioning those 2 first-line endometrial papers are about to be presented. One of them is with dostarlimab. The other is pembro. But I think a lot less experience.

This is really killing me. Okay, 1 more. One more. So, speaking of Ross Camidge, I can’t resist this one, this is from Venu, 69-year-old with Stage IIIe lung cancer, who during the work-up is found to have a Stage IIIb colon cancer. Status-post hemicolectomy. Planning to start concurrent chemoradiation for the lung cancer. So chemoradiation followed by most likely — I would guess durvalumab monotherapy adjuvant. Wants to know, what do you think about adding in FOLFOX6 along with the adjuvant immunotherapy?

DR LIEU: There is plenty of safety data suggesting that you can combine the two. And so, what would be interesting is that you’re treating 2 different indications with 2 different sets of regimens, but would likely be approved, I would assume, just because each one is approved in each tumor type, I would say you should feel comfortable doing that, at least from a safety standpoint. It does hit 2 birds with 1 stone, in the sense that the FOLFOX is going to be giving the adjuvant therapy that you really want to give, and then doing the immunotherapy as adjuvant for lung cancer — certainly, not the expert in regard to that. But I honestly think that makes a lot of sense.

And again, there have been plenty of trials looking at chemotherapy and immunotherapy combinations, from a safety stand, you’re going to be good to go in terms of that. That is a wild case, though.

DR LOVE: It’s amazing what you see in the real world. I’m going to hold off on the patient who’s BRCA2, BRAF-positive. We’ll see whether we can get to that or not.

All right. Let’s get back to our cases first and then hopefully, we can get to these.

Case: A woman in her mid 30s with left-sided T3N0 Grade II obstructing adenocarcinoma of the colon — William R Mitchell, MD

DR LOVE: So we’ve been talking about localized disease and again, people are just trying to figure out what to do with cell-free DNA in the localized setting. We’ve got a couple of cases — I think more questions than answers. This is a 36-year-old woman as I mentioned. Here’s the case from Dr Mitchell.

DR MITCHELL: The patient is 36 years of age, and what happened was she developed an obstructive lesion in her splenic colon.

It was a Grade 2 adenocarcinoma.

Her pathologic stage was T3N0, but she did not have lymphovascular invasion, she did not have perineural invasion, and there was no evidence of perforation.

Would you consider adjuvant therapy for her? She would like to minimize risk; she’s 36 years of age. She’s considering maybe conceiving again. She has 2 children. She’s thinking about pregnancy again if she’s able to.

She also wants to have the reconnection from the diverting colostomy, and she knows that the adjuvant therapy would push her treatment out another 6 to 9 months, and she’s dealing with the bag as best as possible, but it definitely is causing some psychosocial issues with her.

DR LOVE: I see on your list of questions for the faculty about this case the role of CtDNA assays in a patient like this.

DR MITCHELL: I’m intrigued by the data.

I think this may be appropriate to consider that avenue and then subsequent follow up. How do you apply this technology?

DR LOVE: Any thoughts?

DR LIEU: Such a great case and certainly so pertinent now. I’ll use the caveat right now; we certainly need additional data. I do want to highlight the COBRA study, which is being led out of NRG and Dr Van Morris. That study randomizes patients to testing or no testing of ctDNA, and if they get randomized to testing and they’re positive, they get chemotherapy. And if they’re negative, they continue on with observation, which is what our recommendation would traditionally be in this situation. You’ve got a low-risk Stage II colon cancer. We know that there’s likely very, very little, if any, survival benefit of adding chemotherapy. And then there are these other kind of quality-of-life and goals of care issues that Dr Mitchell is mentioning.

Now where does ctDNA fit into all of this outside of the context of a clinical trial? I really kind of think about tests in terms of will it change my management? So right now, your management is to do observation and surveillance. Would the test change what you would do? And we can talk about this in the context of high-risk Stage II or even Stage III colon cancer, but, here, with low-risk Stage II, in the absence of a clinical trial, if you get a ctDNA test and that test is negative, you immediately feel better, right. Get the ostomy reversed. We don’t impact her fertility. She’s good to go. We’re going to surveillance.

But what if the test is positive in a patient that you would traditionally not give chemotherapy to? Who would not give that patient chemotherapy? And I think we’re going to go over later, some data in regard how chemotherapy impacts ctDNA, but I’d like the idea of getting the test and offering treatment based off of the results of that test. Mainly because it would definitely change my management for this patient if I knew she had microscopic metastatic disease present in her blood stream.

Case: A woman in her early 50s with Stage II mismatch repair-proficient sigmoid colon cancer with focal intramural lymphovascular invasion after 6 cycles of adjuvant capecitabine — Priya Rudolph, MD, PhD

DR LOVE: Another sort of snapshot from clinical practice that gets into some other issues, a 50-year-old woman, still pretty young, with Stage II disease. She brings up an interesting issue, I’m curious what your thoughts are, which is actually being able to get this assay done. In this particular case, they were not able to actually do it. Anyhow, here’s the case.

DR RUDOLPH: This patient was 50 years old when she was diagnosed, Stage II. It’s a T3 lesion, N0M0, moderately differentiated, MMR proficient colon cancer. She had focal intramural lymphovascular invasion. 19 lymph nodes were resected with no evidence of metastasis in the lymph nodes.

So based upon the lymphovascular invasion, which puts her at a high risk, we discussed adjuvant chemotherapy, in particular capecitabine for 6 months, which she was very open to.

So she has now completed, will actually finish her last week of capecitabine. Several questions came up as we’re coming to the end of the treatment, the big one being just routine imaging.

Insurance companies fight us every single time that we try to do imaging, particularly if we have documented a negative scan.

Corollary to that, the second question that came up is patients that do develop oligometastatic disease and then have their tumor resected, how often do we image those patients?

The bigger question that is more applicable this day and age is monitoring with ctDNA. I have struggled with getting ctDNA monitoring. The question came up about monitoring her with ctDNA.

There’s really no mention of ctDNA on the guidelines. So I’d love to know how people are doing this, how often are we — should we be checking ctDNA? Is it every 3 months and for how long? And what do you do once you see it?

DR LOVE: And as I said, she had mentioned to me that actually, they were not able to even do the assay because I guess the tumor was all in the colonoscopy specimen and they technically couldn’t do that. How often does that happen?

DR LIEU: So there are a handful of times, a certain low percentage of times where you can’t get enough tumor tissue to do the sequencing to develop the assay to look for those mutations. And we call this tumor-informed testing. Signatera is the most common assay used for that, that’s tumor informed.

To answer that other part of the question, well, what happens if you don’t have enough tumor to do that type of tumor-informed testing? There are also tumor-uninformed tests that are available, that just, kind of essentially the way I can best describe is, it casts a wide net for the traditional mutations or methylation events that you might see in tumorigenesis. And so, certainly the advantage of that is that you don’t need a tumor. The turnaround time is usually faster, 1 to 2 weeks. But, of course, if there’s any disadvantage to that, the sensitivity might not be quite as high as what you see with tumor-informed testing.

DR LOVE: What about her question about imaging? And I guess one of the issues that I hear people talking about in general with solid tumors is can you pick it up when it’s oligometastatic and treat the oligomets locally? And, in the long run, are you better off? But for practical purposes, how do you approach, in general, the issue of screening, of imaging, and also the use of ctDNA in following these people?

DR LIEU: When you look at the NCCN Guidelines, it gives you a little bit of a range. And so, what Dr Rudolph is really mentioning is this idea that insurance, if you try to get a CT scan done every 6 months, they can actually point to the NCCN Guidelines and say, well, we’re only going to approve a year. And if you want to know how I typically surveille these patients, I usually do CEA every 3 months, CT scan every 6 months, if insurance will allow it, for the first 2 years. And then for years 3, 4 and 5, do CEA every 6 months and then annual scans for the last 3 years.

When you deal with insurance issues, there may not be much that you can do to fight with that unless you can kind of prove to them that there’s something like there’s positive ctDNA, or there’s a nodule that I’m looking at in the lungs or the liver that necessitates earlier imaging.

Dr Rudolph had also asked the question, well, what if you do find oligometastatic disease and you cut that out? What does surveillance look like in that situation? And just to give you what I usually do in that situation — I usually do a CT scan every 3 months for the first year after that resection. Then I do every 6 months for year 2. And then for years 3, 4 and 5 I do it annually.

Now, there’s very, very little evidence about the effectiveness of our surveillance techniques and saving lives. But that’s kind of traditionally what we’ve done in the United States, and I’m just kind of giving you what I normally do in a surveillance period for both of those situations.

DR LOVE: So I’m glad we have 3 webinars to work this thing about because it’s going to take 3 webinars just to get through all this stuff.

Let’s try to get through some of the survey in this, and maybe we’ll talk about the data next time. But we like to ask just practical questions in terms of what people are doing, what they’re thinking. So here’s a question of when are using circulating DNA nowadays?

So it looks like everybody at a minimum is doing Stage II. But a couple of people also looking at in select situation for Stage III.

We also, and I’ll ask you for your thoughts about that because you are a Stage II person, then we said, what about a case, kind of like the first case we talked about, no high-risk features? The majority of the faculty said, including you, that they would use ctDNA in that situation.

We also asked them, okay, in that situation, they get an R0 resection. What do you do if it’s — well, negative, it’s not too hard to figure out. But the positive I thought was interesting — everybody says CAPOX/FOLFOX.

So any thoughts about the messages you’re getting in terms of this sort of initial thought about what people are doing right now?

DR LIEU: I think this slide is really nice because it does show very consistent results across all of the faculty members that were surveyed.

One of the things that I find very interesting about some of their responses is, if you go back 1 additional slide, or the one before this, the question of ordering ctDNA in the Stage III setting. So one of the things that I started with was I don’t like to order tests unless it’s going to change what I do. And the problem with Stage III colon cancer is that if you can give chemotherapy, you’re going to give it, right. So if the ctDNA’s positive or negative, it’s not really going to change the management.

When you look at some of the survey results here with Stage III after adjuvant therapy, that’s a very, very tricky situation to be in because if you do a ctDNA test, after you’re done with the curative therapy and it’s negative, you feel great. You and the patient feel very, very comfortable with that data. But the problem is, well, what if that test comes back positive? Then what do you do? And I think that’s the unknown situation that I don’t think a lot of doctors and advanced practice providers want to be put in because there’s not really a great answer in terms of, well, do I switch to FOLFORI? Do I do more frequent imaging?

I think the answer in that situation is that you may do more frequent imaging than you normally would because you’re just looking for where that cancer is going to pop up and then attack it once you see it.

But that’s a very, very tough situation to be in, both as a practitioner and a patient, to not have a very, very clear answer in terms of what to do.

DR LOVE: So any comments — I guess this data initially was presented at last year’s ASCO meeting; got published in The New England Journal. Can you talk a little bit about what was seen here? And how that’s leading to some of the new trials, including the CIRCULATE study that you’re running?

DR LIEU: So the DYNAMIC study is a very, very well-designed study out of the Australian group, Dr Jeanne Tie’s group, and really basically compared 2 different management options: the standard management group, which we just talked about, what would we normally do for low-risk or high-risk Stage II colon cancer? Well, what about the ctDNA-guided group where, if it’s positive results you act on it; if it’s negative results you start to deescalate what you would normally do.

What you’re seeing from this slide here is that the ctDNA-guided management and the standard management arms both did great in terms of 2-year recurrence-free survival and there’s no statistically significant difference between the 2 groups, but when you look at who got adjuvant chemotherapy, you decrease that by 13 percentage points, which means, that patients were not being given chemotherapy but they were doing equally well. And I think that’s the main conclusion from this study is that, hey, if you use ctDNA, they’re going to do just as well as kid of our “standard” management, it’s just that you’re going to give less chemotherapy. And, therefore, that’s obviously a good a thing if we can prevent our patients from getting chemotherapy.

DR LOVE: Yeah, from a clinical point of view, it almost reminds me of Oncotype in breast cancer where the results are maybe not grater outcomes in terms of benefit, but definitely in terms of quality of life.

So this is the publication of the so-called CIRCULATE-JAPAN study. You’re the PI of the CIRCULATE-US study. This study I think is just getting started. We want to encourage clinicians to participate. It’s a fantastic study. Can you talk a little bit about the strategy of both of these studies and in particular, what you’re going to look at?

DR LIEU: Yeah, I’ll start with the CIRCULATE-JAPAN study, the GALAXY arm of that study is really an observational arm. Just looking at, hey, we’re doing serial ctDNA testing and patients are going to get chemotherapy or they’re not going to get chemotherapy. But we’re just going to observe how they’re doing. And I think there’s one major take-home point of the results of this study because they’re testing ctDNA the entire time, and that is, one of our major concerns when these assays were first developed and were out and people were using them was, is ctDNA purely prognostic? In other words, if it’s positive, is it just going to stay positive and our patients are going to recur and there’s nothing we can do to impact that? I think that was our fear, that the test was purely prognostic.

What the results of this observational study show is that if you’re ctDNA-positive, you can clear that ctDNA positivity in about 60% of patients with adjuvant chemotherapy. And what that proves is that if you’re ctDNA-positive, there’s a chance that adjuvant therapy could clear the ctDNA, and if you cleared a ctDNA, you’re going to do almost as well as if you’re ctDNA-negative the entire time.

So, it’s important to understand that these results are somewhat actionable in terms of potentially saving recurrence.

When you look at the CIRCULATE-US study, these are patients with lower-risk Stage III colon cancer. They get ctDNA testing after their surgery, and if you’re negative for ctDNA post-operatively, you get randomized to just getting standard of care chemotherapy, which we would do for Stage III patients, or surveillance. In other words, no chemo, with serial ctDNA monitoring.

If you’re ctDNA-positive, or over time, become ctDNA-positive, you get randomized to standard of care chemotherapy, which is again what we normally do with CAPOX or FOLFOX, but the randomization here is to escalation of chemotherapy with FOLFIRINOX, here it says FOLFOXIRI, but the idea of triplet chemotherapy improve disease-free survival for these patients that we know are going to recur over time.

So this study is open enrolling. And certainly, would love everybody’s involvement with this, if at all possible.

Case: A woman in her mid 80s with pan-RAS wild-type (WT) metastatic rectal cancer with poor tolerance to chemotherapy, now receiving regorafenib with slowly progressive disease — Eric H Lee, MD, PhD

DR LOVE: All right, well let’s continue our rounds here. We’re going to move to another 84-year-old woman. She’s a hairdresser, who loves her work. She says her clients love her. That’s all she wants to do is get back to work and maintain her quality of life. But she’s had multiple therapies for metastatic rectal cancer. Here’s her physician, Dr Eric Lee.

DR LEE: She had very poor tolerance to standard chemotherapy and chose to stop.

She was started on regorafenib, and her maximum tolerated dose is the half dose.

Her PET/CT is showing very slow progression of the metastatic disease. So at this point I’m kind of in a pickle regarding next therapy options. She does not want any form of IV chemotherapy.

She still works. She works as a hairdresser, and she’s happy to take care of her clients every day. So her functional status is pretty good.

She’s fully independent. She drives. She does whatever she wants.

She has never tried an EGFR inhibitor. However, drugs like cetuximab or panitumumab is usually given with a chemotherapy.

Her functional status is excellent. And I’m really trying hard to balance her quality of life, so I’m just trying to line up my ducks in a row to see what’s next.

DR LOVE: So she has not had an EGFR antibody and she’s not had TAS-102. And I guess maybe he could talk her into getting bevacizumab on top of that. But any general thoughts about this case?

DR LIEU: I certainly agree with Dr Lee, that when you have a patient that has very, very clear goals of care in mind, you want to try and match that with the treatment that you’re giving. And just like you said, I really do agree with TAS-102 if she really wants to avoid the Infusion Unit, avoid coming in every 2 weeks to get treatment. Like you said, typically with TAS-102, with the results of the SUNLIGHT study, we would bevacizumab to that. There’s a little bit of a bump in the response rate, although it’s only 6%. But certainly there appears to be a progression-free survival and an overall survival benefit of doing TAS-102 in combination with bevacizumab. If you can convince her to do that, that would probably be something that essentially meets the patients’ goals but isn’t overdoing in regard to chemotherapy.

Again, at 84 years old, the TAS-102 would likely need some kind of dose reduction just to prevent the pretty significant fatigue and cytopenias that you can see with that drug.

In regard to anti-EGFR therapy, here, again, it depends on her willingness to come in every 2 weeks to receive this therapy. But I would be fine with it. It’s not ideal to do it without chemotherapy, but she had pretty poor tolerance as it was to the drug. And so, again, I’d be okay with single-agent cetuximab or single-agent panitumumab in this setting.

DR LOVE: So you could make an argument that the most important paper presented at the GU — GI symposium was the Phase III trial of TAS-102 alone or with bev. As you say, not positive for survival, also, as well.

Case: A man in his early 60s with recurrent, microsatellite stable, HER2-negative, RAS WT rectal cancer, currently receiving TAS-102/bevacizumab — Swati Vishwanathan, MD

DR LOVE: Anyhow, so word’s getting out there right away. Here’s another patient situation where the doc is asking about that issue. And also, what’s your cutoff in terms of giving bev, because this patient I think is on anticoagulation, 62-year-old man. Let’s hear about this case.

DR VISHWANATHAN: He’s 62. He had prior history of Stage III rectal cancer. Underwent chemoradiation, resection, and finished adjuvant chemotherapy and had recurrent disease after 3 years with hypermetabolic para-aortic and inguinal adenopathy. The para-aortic lymph nodes were biopsied and they were proven to be recurrent rectal cancer.

And we have initiated TAS-102 and he’s had 2 cycles so far.

Questions pertaining to this: Are they routinely using bevacizumab and TAS-102 in combination? In what setting would they use the two? In this case I was hesitant to use bevacizumab because he also had DVT/PE, requiring anticoagulation and he also had a fistula.

If he didn’t have those relative contraindications would our panel routinely be using TAS-102 bevacizumab combination? And what would be his options if he progressed both on TAS-102 and regorafenib?

In fact, in your, one of the webinars, you had discussed, there was mention of a new drug fruquintinib. I don’t even know if it’s available to us.

How are the experts navigating that decision? What would they do if a young patient like him, who had good performance status, progressed on all the other available options?

DR LOVE: And I’ll add the question of are you more likely to want to use bev with TAS-102 if the patient long responses to like, FOLFOX/bev or other — with bev or FOLFORI/bev?

DR LIEU: Yeah, this is a s real-world as it gets, right, in regard to patients who have exhausted their therapy options and now we’re trying to figure out, well, what happens at the time of progression when we’re kind of running out of standard of care options. And obviously, clinical trial consideration is something that can occur at this point, right, but the problem is that there may be no clinical trials available. And there are a lot of clinical trials that don’t allow anticoagulation or allow fistulas.

To answer Dr Vishwanathan’s question in regard to bevacizumab. In regard to anticoagulation in the DVT/PE, a little bit less concerned about that if the patient’s been on anticoagulation for quite some time and has been stable, without any bleeding issues. But she’s right in regard to the fistula, that’s a really tough situation to give bevacizumab on, because you just worry if that gets any worse — I mean we’re dealing with all kinds of problems, not the least of which are infections and then certainly quality-of-life issues. But when you can add bevacizumab to TAS-102, it’s great if you can do it.

One of the caveats of the SUNLIGHT study that was presented at GI ASCO, was that 30% of the patients that were enrolled onto that study had never received bevacizumab. So one of the concerns is, some of the great results that we’re seeing in that study, how many of those great results are from patients that had just never received bevacizumab before? And that’s just one of the things. But to your point, Dr Love, if somebody’s had great responses on bevacizumab for a long period of time, you do kind of believe that that patient is really benefiting from anti-angiogenic therapy.

And to answer the question about fruquintinib, the FRESCO-2 study was presented by Dr Dasari at ESMO this year, showing an overall survival benefit with the use of fruquintinib, which is a VEGF-R/TKI, and this is in the fourth-line setting, right. So the study population were in patients that have received third-line treatment. Fruquintinib, it’s going to come up for FDA approval. It is currently not available. But it is something that everybody should have on their radar in regard to potentially a fourth-line option for metastatic colorectal cancer. It’s kind of wild that we’re talking about that. But that is currently not available, but something that people should be aware of in regard to fruquintinib in colorectal cancer.

DR LOVE: I guess it’s going to be the first VEGF-TKI in colon cancer, right? I mean there aren’t any now, right?

DR LIEU: Yeah. It depends on what you think about regorafenib. Because regorafenib…

DR LOVE: Yeah. No, you’re right. Regorafenib. Okay.

DR LIEU: Because reg, it hits a lot of targets. So there’s a lot of mechanisms of action.

DR LOVE: You’re right. It is a TKI. Okay. I know.

So let’s just quickly take a look at some more questions from the survey. This I thought was really interesting. I was telling you, our way of doing a consensus is, we ask people what they do. If they all do the same thing we call it a consensus. And I was pretty surprised. We’ve been seeing more and more EGFR antibodies first-line in left-sided lesions. And here, most of the people, including you, say they tend to favor it. I’ll ask you for your comments in a second.

Also, I don’t know whether it’s because of the new data, but in the past people kind of went back and forth about what comes first, regorafenib or TAS-102. Now people seem more inclined to go with TAS-102, particularly with the bev before regorafenib. And it looks like the faculty, in general, survival benefit, they’re adding the bev.

And finally, the issue of rechallenge with EGFR antibodies, which everybody does. There was data looking at ctDNA. Maybe you can comment on that.

Any thoughts about these parts of the survey?

DR LIEU: I think with the presentation of the PARADIGM study at the Plenary session at ASCO, looking at the combination of chemotherapy and anti-EGFR therapy for left-sided, RAS wild-type colorectal cancer, I think there’s increasing evidence that if you have — essentially, this is about 15- to 20% of our population, so it’s not like this huge patient population, but you’re looking for, what, left-sided tumors, RAS/RAF wild-type, microsatellite-stable, typically HER2-not amplified, there’s a cohort of those patients that we really think are going to respond really, really well to chemotherapy and anti-EGFR therapy. And you can see that that there’s an overall survival benefit.

Now the difficulty, I think, is that it’s just a lot easier for patients to tolerate traditionally bevacizumab, as opposed to anti-EGFR therapy. We also know that the anti-EGFR therapy side effects do get better over time, but sometimes patients just have these horrible reactions to anti-EGFR therapy.

So I think that there’s some hesitancy, which is certainly understandable, across many groups in regard to starting anti-EGFR therapy first. But it does appear that the responses can be pretty robust with chemotherapy and anti-EGFR therapy.

And then you saw some slide in regard to the PARADIGM study. And then, what you’re looking at here is a publication of TAS-102, with or without bevacizumab. And this was a Phase II study that really provided the background data needed for the SUNLIGHT study, which is this study, where patients with 2 prior regimens were randomized to receive TAS-102, with or without bevacizumab. And when you look at overall survival at 10.8 months in this setting, I mean this was some of the higher, or highest overall survival that we’ve seen in a heavily pretreated population. Again, this data, I think, just really backs up what we’ve known for maybe about a year or 2, is that when we can add bevacizumab to TAS-102, we should do that.

I had actually made mention of this overall response rate, again I wouldn’t expect a tremendous response or shrinkage of tumor with the combination TAS-102 and bevacizumab — or of — yeah — bevacizumab. One of the things that Dr Love had mentioned was anti-EGFR rechallenge. We also sometimes rechallenge patients with the chemotherapies, right. If it’s been 3 years since somebody’s received FOLFOX or CAPOX, you can actually rechallenge those patients with chemotherapy and sometimes get a response even though those responses are typically not super durable.

And then finally, the FRESCO-2 study, which we had mentioned, of fruquintinib. This is just certainly a drug that we want to keep on everybody’s radar because, again, we’ll see what the FDA says about this. But we’ll be looking for this drug potentially in the future.

DR LOVE: Just to clarify though, about the EGFR rechallenge. That’s also based on liquid biopsy being negative for KRAS mutation?

DR LIEU: What’s wild is that I’ve had patients on cetuximab or panitumumab and obtained ctDNA testing while they’re on therapy, and I’ve gotten ctDNA reports that show a KRAS mutation, an NRAS mutation and a concurrent BRAF mutation all in a patient that was completely wild-type, right off of the tumor tissue testing. It really just shows you that when you stress the tumor and the body with targeted therapy, you do see the emergence of some of these mutations that do confer resistance.

A lot of now will actually recheck the ctDNA and if the patient remains RAS and RAF wild-type, that’s the patient population that I’m most excited about in regard to anti-EGFR rechallenge.

Case: A woman in her mid 50s with RAS WT, HER2-amplified metastatic colon adenocarcinoma — Gigi Chen, MD

DR LOVE: So, HER2-positive colorectal cancer. That’s not something we’ve been talking a lot about. All of a sudden, we’ve got 2 options to talk about. We just did a 2-hour program on HER2-positive lung cancer. So, not totally surprised. But, of course, everybody has questions. We’ll start out with a patient of Dr Gigi Chen, 54-year-old woman, RAS wild-type, metastatic disease, but HER2-amplified.

DR CHEN: This is a 54-year-old woman. She had initially presented with iron deficiency anemia. She underwent workup, which showed an ascending colon cancer. And surgery showed a Stage IIIB (pT3N1a) colon cancer, mismatch repair protein intact.

She completed adjuvant chemotherapy with CAPOX for 3 months and she had a recent CT scan that demonstrated new liver lesions. And she was evaluated by surgical oncology, and our plan at this time was to start chemotherapy with FOLFIRI followed by liver-directed therapy.

And I just got her next-generation sequencing back a few days ago. That showed that she is KRAS wild type, NRAS wild type, but she did have ERBB2 amplification. So my question to the group, or to the investigators, is that what would be the best treatment for her, given her ERBB2 amplification.

DR LOVE: So I can tell you I’ve heard cases from Dr Chen where she’s used T-DXd in breast cancer and I’ve heard cases where she’s used tucatinib with capecitabine/trastuzumab in breast cancer. And now, all of a sudden, she’s trying to figure out what to do with this lady. Any thoughts?

DR LIEU: So this is really an interesting situation. HER2-amplification, we see this in about 3- to 4% of our patients with metastatic colorectal cancer. It’s rare but it’s targetable. It’s amazing that 1 or 2 years ago we weren’t even really thinking about HER2, right, or testing for it. And now it’s something where, especially in our RAS and RAF wild-type patients, that should immediately make you think about HER2-amplification and make sure your patients are tested. Because, again, the RAS/RAF wild-type population, that’s the population that we’re trying to really find these HER2-amplifcations and target them.

Traditionally, when we have oligometastatic liver disease, what do we want to do? Give chemotherapy. Do surgery and potentially some chemotherapy afterwards.

What’s interesting, is that in this setting you can kind of thin about FOLFIRI as a second-line agent, just because the recurrence happened either shortly after or on CAPOX. When you look at the second-line data for colon cancer — metastatic colon cancer, the response rates of FOLFIRI in combination with the biologics, usually somewhere between 15- to 20%. When you look at the small Phase II studies that have been done in HER2-amplified colorectal cancer, now you’re looking around that 40% to 50% response rate.

So if the goal is really to shrink the cancer, believe or not, I think it’s kind of hard to believe that I’m actually going to say this, but I actually kind of like the HER2-directed therapy, mainly because of 2 things: number 1, at least in the smaller subsets, the HER2-directed therapy has higher response rates and that’s what we’re really going for in order to make patients surgically resectable. The second thing is, well, if the anti-HER2 therapy doesn’t work, you’ll know within 2 months, and then you can revert back to FOLFIRI and use that to try and get patients onto surgical resection.

Again, I think it’s hard to do cross-trial comparisons whenever you’re looking at the HER2 studies, which are really, kind of comparatively small, compared to the studies that we have for chemotherapy. But in this situation, you’re trying to maximize response. And I see anti-HER2 therapy as the best way to do that.

DR LOVE: So tucatinib/trastuzumab, or T-DXd, if you could?

DR LIEU: Tucatinib/ trastuzumab. Recently it was FDA-approved. In fact, when we were at GI ASCO, that announcement came out right around then. So it was actually really, really great to see.

If you want to maximize response, again hard to do cross-trial comparisons. But, with trastuzumab deruxtecan you do have, at least numerically, a slightly higher response rate, but you pay for that in terms of increased toxicity.

I would say in this situation if we really did need a great response in order to get to surgical resection, I would actually start with trastuzumab deruxtecan, which is something I don’t traditionally do. When you look at how we sequence therapy in HER2-ampliified colorectal cancer, I like to start out with trastuzumab/tucatinib and then move on to trastuzumab deruxtecan. Because about 40% of the patients in the DESTINY-CRC study had prior anti-HER2 therapy before receiving trastuzumab deruxtecan. And it kind of gives you some basis to say, well, even if I start with trastuzumab/tucatinib, or pertuzumab or lapatinib, I might be able to salvage them with trastuzumab deruxtecan.

DR LOVE: Chatroom saying, how about FOLFIRI plus trastuzumab, like à la TOGA? Also, the chatroom wants to know what’s the best way to test for HER2? But it’s the same as breast, IHC and FISH?

DR LIEU: Yeah, IHC/FISH. NGS has a really good capture rate. There is probably about an 8- to 10% miss rate of NGS and identifying HER2. There are times where I’ve gotten NGS and I’ve sent out the HER2 FISH just because I wanted to make ultra-sure. I’ve never seen a miss yet by NGSS, but I’m just talking about some of the retrospective reviews that have looked at this.

And so, in terms of chemotherapy and these agents, I think that might be the next step to maximize response. It would be interesting to see FOLFOX/trastuzumab/tucatinib, FOLFIRI/trastuzumab/tucatinib, and actually, those studies, believe it or not, are actually ongoing. So we’re going to have an answer probably sooner than we might realize. But right now, I have a hard time recommending that in the absence of even early data.

Case: A woman in her mid 60s with multiregimen-relapsed RAS WT, HER2-positive metastatic rectal cancer, now receiving trastuzumab/tucatinib — Sunil Gandhi, MD

DR LOVE: So let’s do another HER2 case. This is actually a patient who’s getting trastuzumab/tucatinib, a 66-year-old woman. Before we hear about the case, I’m just kind of curious what you’ve seen in terms of tolerability with trastuzumab/tucatinib?

DR LIEU: I’ve actually been very, very impressed with the tolerance of both of these drugs. My patients, I haven’t actually had any severe side effects. We all, certainly, very well aware of trastuzumab — and those of you who treat a lot of breast cancer certainly have used tucatinib in the past — but I’ve actually found the regimen to be very, very well tolerated.

DR LOVE: Yeah, the problem with breast cancer is the HERCLIMB regimen, they include capecitabine. So here, you’ve got just the trastuzumab. And then you get diarrhea, et cetera, et cetera.

Anyhow, here’s I guess a case for the future, Dr Gandhi from the FCS is already all over all of this. This is a patient who’s on the second form of anti-HER therapy already, a 66-year-old woman.

DR GANDHI: This patient had a rectal metastatic cancer on presentation.

Liver and lung mets. It was HER2 3+. Treated her with FOLFOX and bevacizumab. She responded very well initially. And then, she had disease progression. So then, we switched her to FOLFIRI and cetuximab. And after, she did not respond that well. And that is when I went to T-DXd. And there was initial response and that lasted for 6 months. And then, she had disease progression on T-DXd.

We gave trifluridine and then later on, regorafenib. She has progressed. And I was about to advise hospice and then I read this new approval of trastuzumab + tucatinib. So I just, just started that drug maybe a week ago.

DR LOVE: Have you used tucatinib in breast cancer?

DR GANDHI: I had one patient that I can clearly remember off the top of my head.

She had a brain met after we gave the treatment. And I went with tucatinib on that patient with capecitabine. And my goodness, we did not even give radiation. She pulled it on for about 1 year, maybe a little longer without radiation, brain met improved by MRI. So I liked it.

DR LOVE: So, yeah, that’s the other thing in breast cancer, they’ll treat without radiating because they see — that’s what they did in the trial. I don’t know if we know anything about CNS activity in colorectal cancer. But any comments about this case? I mean this patient’s already had like 6 lines of therapy.

DR LIEU: Right. No, it’s really, really impressive. And obviously, it really depends on the patient’s performance status. Because you do wonder if, in any way, recycle FOLFOX, depending on how long ago it was given. Dr Gandhi had mentioned this idea of giving anti-EGFR therapy, which makes sense because the patients are RAS and RAF wild-type. There is some data to suggest that HER2-amplification actually confers some resistance to anti-EGFR therapy. His case actually does reflect that. But there’s some controversy because we don’t know that for a fact. And I wouldn’t necessarily put it as an absolute no for anti-EGFR therapy. But I do have the same concern, based on with Dr Gandhi’s patient, where the patient did not respond very well to FOLFIRI and cetuximab.

It’s interesting, we had talked about going from trastuzumab/tucatinib to T-DXd, but we really don’t have a lot of experience with T-DXd, and then receiving trastuzumab/tucatinib. Interestingly, I have a patient very similar to this who I am trying that, now that tucatinib is FDA-approved. But the problem is that we don’t really know what the response rate could be. Is it worth trying? It is because the patient wants to receive it. And there really aren’t a lot of active regimens here, in the absence of a clinical trial. So, I’m actually all for it. But I think we need to get that data to determine if this is something that we should be doing because we don’t have any clue right now.

DR LOVE: So some more from our faculty survey. We say, when would you bring in anti-HER therapy, in general, metastatic, HER2-positive disease? And people are saying mostly second line, which I think is very interesting.

We say, what targeted therapy, in general, anti-HER therapy comes first? Everybody, — well no, Dr Deming says trastuzumab/pertuzumab. That always sneaks in there somehow. Everybody else says tucatinib.

And then, more T-DXd second line. Just as you were saying, really because of toxicity consideration.

We said, what about a patient with brain mets? Everybody, except you, said tucatinib. We get the same controversy in breast cancer, second-line therapy with brain mets. There’s always argument about that.

And then, finally, we said, what about a patient who gets FOLFOX/bev, HER2-positive disease, and then has disease progression? What’s coming next? Again, kind of reflecting what we’ve just been talking about.

You see a few different answers, but, again, the most common answer, tucatinib/trastuzumab.

Any thoughts about your and your colleagues’ approach?

DR LIEU: Yeah. It would have been very interesting to see what these results looked like prior to Dr Strickler’s presentation of the MOUNTAINEER data, which was tucatinib and trastuzumab, and then the FDA approval. Because I bet you would have seen a ton of trastuzumab/pertuzumab. I think you have seen a lot of trastuzumab — or maybe some trastuzumab and lapatinib. And again, that’s really from single-arm, Phase II data, but again, I think the best data, and obviously, the FDA accelerated approval was tucatinib and trastuzumab.

So these survey results I think would have looked different in mid-2022. They look very different, obviously, now that we have the FDA approval.

In terms of the sequencing of therapy, it just really depends on how your patient is doing. I think what you’re seeing reflected in the survey is that patients really want to try and give that targeted therapy up front. Maybe leave something like FOLFIRI and bevacizumab or FOLFIRI and cetuximab/panitumumab as a back-up option. And then, also, leaving trastuzumab deruxtecan also as a back-up option.

So it’s kind of interesting that you’re seeing this. But there’s no right answer to this because nobody really knows the answer. I think what you’re seeing is also reflective in the BRAF data, which, I don’t think we’ll have time to get to, but this idea of trying to push those targeted therapies earlier in line, where, hopefully, they’ll work better, and then using chemotherapy as a backup.

DR LOVE: Yeah. I was just thinking about what it’s like to be in oncology nowadays. Here we have you trying to choose. You’ve got docs asking about this. The data was presented for the first time last summer. Last summer! The first time it was presented! Now it’s FDA-approved. We’ve got alternatives. Really amazing being in oncology.

All right. Well, let’s see if we can sneak in a couple of MSI or at least 1 case, MSI BRAF. We were talking about these data. You can check out our slide set and the papers relative to them. This is a water fall plot for the MOUTAINEER study. I think pretty impressive, at least. And I think these tolerability issues are what people expected. You mentioned the data that was presented by Dr Strickler at the ESMO, following up on that.

Case: A woman in her late 70s with HER2-negative, BRAF V600E-mutant, microsatellite stable metastatic colon cancer after mFOLFOX/bevacizumab followed by maintenance 5-FU/bevacizumab — Victoria Giffi, MD

DR LOVE: But let’s see if we can sneak in at least 1 case. So we’ve got a 77-year-old woman who’s BRAF-positive and status-post FOLFOX/bev. Let’s hear what Giffi has to say about this 77-year-old woman.

DR GIFFI: Her colonoscopy found an ascending colon lesion. Biopsy confirmed adenocarcinoma. Her HER2 was negative, MSI stable, and she was found to have a BRAF V600E mutation.

She had bilobar liver metastases and a lot of pelvic and abdominal adenopathy. So she was started on FOLFOX and bevacizumab chemotherapy, had to stop the oxaliplatin after 11 doses due to pretty severe neuropathy, and she remains on 5-FU/bevacizumab maintenance.

She had a decent response. You can see on this PET/CT that her liver metastases came down quite a bit after just 6 cycles, and she received 11 total.

DR LOVE: So what are the questions you have about her?

DR GIFFI: I’m curious is anyone looking at giving BRAF-directed therapy in first line instead of second line.

Do we know any more about the mechanisms of resistance to BRAF-directed therapy in BRAF-mutated colon cancer?

DR LOVE: So, yeah, reflecting what you were just saying. Any thoughts about where things are heading?

DR LIEU: So there was the ANCHOR-CRC study. It looked at a triplet combination of binimetinib, encorafenib and cetuximab. The results were okay. It’s kind of actually what we would expect with front-line chemotherapy. More interestingly, at ASCO, the initial safety lead-in for the BREAKWATER study were presented at the ASCO Annual meeting, and that looked at chemotherapy, FOLFOX or FOLFIRI, in combination with a doublet, encorafenib and cetuximab. And the results were actually pretty outstanding. Response rates were in the 70%, which is wild for this BRAF population.

So what we’re going to see with the BREAKWATER study is them moving forward with FOFLOX in combination with encorafenib and cetuximab. And we’re going to see how these patients do.

So the story is yet to be written. Is this something that we can do now? No. We still use encorafenib/cetuximab. I like to use it in the second-line setting. That’s where I think it should be used, if possible. But it’ll be interesting if we start seeing patients treated with a combination of chemo and a targeted therapy all at the same time. But, again, that data will be coming in the coming year or two.

DR LOVE: So I’m going to save this next case here from Dr Azzi, who’s got a KRAS G12C. I’ll save that for Dr Strickler for next time. But I do want to close out because we have a KRAS G12C question in the survey that I want to get your take on, on your thoughts about this final part of the survey. Your thoughts.

So, first-line therapy in metastatic MSI-high? Most people are saying pembro. Ipi/nivo comes up, as always, from one of the docs.

We also asked about what first-line treatment is? I’ll call this sort of a consensus, FOLFOXIRI/bev. I’m not sure everybody’s doing that necessarily in their practice. Most people right now are using a second-line targeted therapy, as you mentioned. And again, I’ll call this a consensus, being encorafenib and EGFR antibody.

Finally, adagrasib — actually, we had this case where the doc actually managed to get sotorasib and cetuximab, somehow. I don’t know how they got it.

But any thoughts right now about these? And what are you doing with the KRAS G12C/ Outside a protocol setting have you tried to do one of these agents with an EGFR antibody?

DR LIEU: So we have, obviously, these clinical trials here and certainly see a significant improved response rate when you use the doublet of KRAS G12C inhibition with, like cetuximab or panitumumab. It’s interesting. What you’re probably seeing in the poll are patient’s experience with the agents in clinical trials. I have not been able to get it off-label. But if I did, I would definitely use the doublet. I would not use single agent. If you can do the doublet, that’s definitely the way to go, at least based off of the initial data and the data that we saw in The New England Journal of Medicine paper.

DR LOVE: This doc, when we presented a case of his, somehow he got enfortumab and pembrolizumab first-line in bladder cancer. So, he must have — I don’t know how he gets his stuff, but he’s on top of it for sure.

Anyhow, Chris, thanks so much for working with us today. It was so informative. So exciting to see all these changes.

Audience, thank you for attending. Come on back tomorrow night. We’ll see if Dr Konecny can update us or straighten us out about the crazy world of PARP inhibitors in ovarian cancer. And I’m really looking forward to hearing what Dr Patel has to say. Hopefully, he’ll be able to explain, at least to me, how tumor treating fields work. From what I can tell, maybe the world’s expert. So I want to understand about it more and I invite you to join me tomorrow night.

Chris, thanks again.

Be safe. Stay well. And have a great night.

DR LIEU: Thank you, everybody.

DR LOVE: Have a great day. Thanks a lot, Chris.