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Benjamin L. Schlechter, MD: Hello. I'm Dr Benjamin Schlechter. Welcome to Medscape's InDiscussion series on colorectal cancer. Today we're discussing treatment options for refractory colorectal cancer with Dr Cathy Eng. Dr Eng is a professor of medicine, hematology, and oncology at the Vanderbilt-Ingram Cancer Center, as well as the co-director of gastrointestinal (GI) oncology and co-leader of the GI cancer research program. She's also a recognized expert in colorectal cancer and a prolific clinical trialist. Thank you for joining us today. It's great to have such a distinguished guest.
Before we start to talk about these treatment options for refractory colorectal cancer, can you first tell us a little bit about your path to becoming a GI oncologist?
Cathy Eng, MD: I was trained at University of Chicago and was exposed to GI medical oncology at that time. I originally was a head-neck fellow, so it wasn't a clear path. I went to MD Anderson to look at a job position, and I ended up taking it. That is how I became a GI medical oncologist. Things changed a little bit in my career. It seemed like a great opportunity, and it was at the time when a lot of new drugs were becoming available to patients with colorectal cancer. It wasn't just 5FU anymore. I looked at the landscape and decided that was what I wanted to focus my career on.
Schlechter: That seems to be a theme as we go through these interviews with all these distinguished oncologists. Not a lot of people start their career thinking, I want to be a GI oncologist, but many of us see the light. I had the same path. I thought it I was going to be a lymphoma doctor. Now I'm a very happy colorectal oncologist. It is part of the story. I think it's so important that we expose fellows, for example, to these drugs and diseases so they can find the inspiration and really seek to treat them.
Let's move to the topic today, which is refractory disease. I think for the purpose of this discussion, we should define refractory colorectal cancer. For today, let's just call that colorectal cancer patients who have had prior fluoropyrimidine, oxaliplatin, irinotecan, and a monoclonal antibody such as bevacizumab, panitumumab, or cetuximab as appropriate. Beyond targeted therapies for rare things like BRAF and HER2, our options are limited. We are treating patients with trifluridine with tipiracil, plus or minus bevacizumab with regorafenib, and most recently with fruquintinib. Let's first talk about trifluridine with tipiracil (TAS-102). The initial phase 3 data for this came out of the RECOURSE study in The New England Journal of Medicine by Dr Mayer and colleagues. This was a very large, randomized trial that looked at trifluridine vs placebo in refractory colorectal cancer. There were several interesting findings from this. First, it looked at performance status as an endpoint, and I think this is a helpful metric in advanced disease. It also showed that trifluridine with tipiracil delayed progression of worsening of performance status. Patients' performance status was maintained for 1.7 months longer compared with placebo, and that was statistically significant. It is a 7-week benefit, but that is meaningful in very advanced disease. There was also an improvement in overall survival to 7.1 months from 5.3 months, but the progression-free survival (PFS) data was really a 2-month benefit vs 1.7 months benefit. So, a benefit, but a limited benefit. In your experience with trifluridine with tipiracil, how do you use this drug with patients? How do patients respond to this agent?
Eng: I'm presuming that you're talking about just single-agent use and not combination.
Schlechter: Let's start with single agent. We can talk about the combos later.
Eng: For single-agent use, that's obviously a very select setting because we do have data, as you're going to mention later on, in combination with bevacizumab, where it appears to be more beneficial. There are some patients who cannot receive bevacizumab because of having fistula formation or maybe some other medical condition that does not make them a good candidate for anti-VEGF therapy.
When I think about utilizing TAS-102, it does have an advantage in the sense that it's an oral agent. That is quite beneficial regarding quality of life for patients, so they don't have to travel back and forth extensively for an IV injection.
As you've seen in the data, and as many of our listeners may know, there is concern about myelosuppression. That is one component that really needs to be followed closely for individuals that are placed on this agent. I would say that most of us probably try to find a clinical trial for our patients when we're thinking about the third-line setting and moving forward. But if I don't have any clinical trials available, I do consider oral agents such as this and others that we're going to mention later on, kind of like a bridge until a clinical trial is available. I think overall, excluding the myelosuppression, it's tolerated very well as a single agent. I think that's meaningful for a patient, because once again, we're talking about patients who are surgically unresectable with metastatic disease. We want to be able to provide them whatever options we have available to us, that are tolerated well, with good quality of life to improve their overall survival.
Schlechter: How do patients do in terms of navigating this drug? It's kind of a funny schedule.
Eng: I think that's a great question, and it is something that we have to be very careful around. Patients need to be well educated. I remember one of my very first patients who received this treatment. Even though she met with our PharmD and was given explicit instructions, she somehow misheard us and did not read the information provided to her. She took the medications, including doses on the weekends, and ended up with severe myelosuppression and grade 4 neutropenia. She felt horrible, unfortunately, and that's because she didn't follow the schedule, which is days 1-5, 2 weeks in a row. The way I like to give it is 2 weeks on, 2 weeks off. Patients take the medication for 5 consecutive days for each of those 2 weeks. I like to give it Monday through Friday. I think that's the easiest way to remember how to administer it for patients. They really need to have a calendar in front of them, to ensure that they are taking it appropriately.
Schlechter: I always try to get the Monday through Friday dosing as well, but it's hard because I don't see patients on Monday, for example. I've sat down with patients with a calendar as well. I find that useful. I think sitting down with patients with a calendar is helpful and getting pharmacy support is helpful. So that's great insight.
Eng: Thank you.
Schlechter: You mentioned the addition of bevacizumab and I think that's really important. Let's talk about SUNLIGHT for a second. SUNLIGHT looked at trifluridine plus or minus bevacizumab. This was also published in The New England Journal this past year by Prager and colleagues. This was conducted in both Europe and the US and looked at the addition of bevacizumab. Here again, we have a positive trial in refractory colorectal cancer, which obviously is always encouraging. The overall survival was increased to 10.8 months from 7.5 months. PFS was also increased to 5.6 months from 2.4 months. Honestly, the results of SUNLIGHT look pretty good to me compared with trifluridine alone, but it's still a pretty modest benefit and there seems to be good evidence that the addition of bevacizumab helps here. How do you think about these data? Are you using bevacizumab routinely? Is that your go-to in this combination?
Eng: Great question once again. I have to be honest: Many of us have been utilizing the combination with bevacizumab since the original phase 2 study was published, because it resulted in an approval for NCCN guidelines. As a result, many of us felt comfortable moving forward in that fashion.
As you mentioned before, with just single-agent use, there was only a difference of 1.7 months. When we saw the phase 2 data, we felt that that was the most promising. I think many of us started using it for any patient who is a good candidate for bevacizumab. That is why, if you look at the SUNLIGHT demographics, you'll see that a smaller component of the patients were from the United States. Most of the patients were overseas for the study.
Schlechter: Are there any findings related to people who seem not to benefit from this trial, or is this a pretty good combo across all subtypes of colorectal cancer?
Eng: You want to have a compliant patient with good bone marrow and great blood counts before pursuing this regimen, and they need to be followed closely in regard to their blood counts. But I would say overall, based upon the data that we have currently, there's not any particular patient that should not benefit from it unless, once again, they have significant myelosuppression at baseline or they're not a good candidate for bevacizumab. We all know that there are several contraindications — for example if you've had a recent cerebrovascular accident or myocardial infarction or other medical problems that may be hampered by utilizing bevacizumab. We don't want to use that combination.
Schlechter: Excellent. It is helpful to have a drug for refractory disease that's sort of agnostic to left vs right, and agnostic vs RAS, a mutation, or wild type — things like that. Although probably by this point most patients have acquired a resistance mutation.
Eng: I do want to mention, though, that that trial was specifically for the third-line setting relative to other trials that have been conducted.
Schlechter: That's a very important point. This is a very heavily pretreated population and yet patients really did benefit. At least in my clinical practice, I do find the agents helpful. I have a subset of individuals with prolonged disease control, but objective responses — I don't know if I've ever really seen an objective response with trifluridine.
Eng: I would say not by RECIST criteria, by any means, in regard to what we expected from a clinical trial. But yes, I would say that I've had a lot of long-term patients but not a dramatic reduction in tumor burden.
Schlechter: The other member of this trifecta of refractory colorectal cancer agents is regorafenib. This has been a challenging drug for a long time for those of us who treat these patients, because it's a tough drug. The CORRECT study was published in The Lancet in 2013; Dr Grothey and colleagues were the authors.
This looked at full-dose regorafenib, 160 mg daily, 3 weeks on, 1 week off. That was done vs placebo. There was also the CONCUR study in Asia, published in The Lancet Oncology by Li and colleagues, with very similar findings. What they found was a minimal increased overall survival of 6.4 months vs 5 months. And the PFS was nearly identical: 1.9 vs 1.7 months. It was a limited benefit with this agent. Half of the patients had some sort of grade 3 toxicity. Where do you fit full-dose regorafenib, 160 mg, into your practice, if you fit it at all?
Eng: The only time I utilize full-dose regorafenib is when I have to as part of a clinical trial as a standard-of-care arm. And that's because it's in the FDA insert. If I utilize regorafenib, I never utilize it at the full dose. I always start off at a lower dose. I think you're going to mention the ReDOS trial from my colleague, Dr Saab. We have learned that after the regorafenib was approved, there are associated toxicities that are very difficult for the patient to bear. We need to start them off at a lower dose in order for them to tolerate the drug well and to have benefit. If a patient stops the drug prematurely before they even get restaged, it benefits no one. In those cases, the patient is not feeling well at all, so it's a quality-of-life issue. I fully recommend a dose reduction before initiation of any further therapy.
Schlechter: That was one of the interesting findings in the CORRECT study; they did look at quality of life the same way the trifluridine studies did. The quality of life in the treatment and nontreatment arms was about the same. Essentially, patients who were getting sicker from cancer and getting sicker from getting regorafenib kind of had the same quality of life, which is always a disturbing finding.
Eng: If I recall, I think the median lines of prior therapy were very high: four or five prior lines of therapy, if I'm correct. At that time, we just didn't have a lot of treatment options, to be honest. When the drug was approved, it provided us another option, right?
We're always looking for options for our patients to improve their overall survival, and at that time it seemed very reasonable. But it was a very heavily pretreated patient population from what I can recall.
Schlechter: It was a heavily treated population. It was a tough drug, but I think it was an important innovation. I think it's gotten a lot of negative press, but at the same time it's an effective drug. You referenced the ReDOS study. I think that's actually a really important innovation in this agent. ReDOS looked at regorafenib in 160 mg, the full dose, vs a dose-escalation strategy starting at 80 mg a day for a week, and then going week by week to increase up to 160 mg as tolerated. Most patients land around 120 mg. That was also in Lancet Oncology by Dr Saab, as you said, published in 2019. For me, that really improved general access to regorafenib. The other thing that was built into the ReDOS study was prophylactic clobetasol, where patients were randomized to receive clobetasol to their hands and feet vs no clobetasol. It could be reactive or prophylactic. Unfortunately, that didn't show a huge impact. That was published in The Oncologist in 2021. Are you using this as an approach for your patients with refractory disease?
Eng: Utilizing clobetasol?
Schlechter: No, utilizing regorafenib and clobetasol.
Eng: Whenever I consider regorafenib, I do consider the reduced dose, as suggested by ReDOS. I think it's very, very reasonable to consider that for patients. And then I feel more comfortable moving forward, if I do utilize regorafenib. I have not historically been utilizing clobetasol as prophylaxis.
I have utilized it in select settings, but not from the get-go, to be honest. I think with the starting dose being reduced, it really decreases the risk for hand-foot skin reaction, and we don't have as much of an issue with having to use clobetasol. That's why I've not utilized it for prophylaxis.
Schlechter: I don't use it either. The other interesting finding about the ReDOS study was there was a trend toward improved survival; it was not statistically significant, but I think that's meaningful. Patients received more cycles of therapy because of ReDOS. How do you see that information?
Eng: I think it's a really important study, in the sense that even though it was not a big phase 3 study by any means, it was informative. It really changed practice patterns. I think it's a practical application from literature, which we don't necessarily see a lot, where they try to revise the dose.
I mean, look at capecitabine, which many of us have been giving for years. None of us use full dose. I think it was a very important paper to educate practitioners on how to treat patients appropriately without harming them. I'm fully supportive of that approach.
Schlechter: It's a great point about capecitabine. I could probably do a whole podcast on capecitabine. I have a love-hate relationship with capecitabine, as many GI oncologists do for so many reasons.
Eng: I think that's another topic.
Schlechter: Capecitabine is an interesting drug. It was a great attempt at a logical design for a fluoropyrimidine, and I wish it were as good as it should have been.
Eng: I think we have to remember when it was approved, right? It was really when there were no options.
Schlechter: We live in an era where we have good-enough science that we can design better fluoropyrimidines. There are some companies out there that are working on that. I hope that we have a chance to talk about the new 5FU someday, because if we could improve 5FU, that would be great for so many patients.
Eng: I agree.
Schlechter: Let's talk about fruquintinib. This is an interesting drug. Like regorafenib, it's a multifunctional VEGF tyrosine kinase inhibitor (TKI). Like regorafenib, it's a 3-weeks-on, 1-week-off dosing. It's reasonably simple and straightforward for patients to take. We had the recently published FRESCO-2 trial in The Lancet, led by Dasari and colleagues.
This showed an increase in overall survival to 7.4 months from 4.8 months with a PFS increase to 3.7 months from 1.8 months. It's hard to make comparisons between trials. And frankly, we probably shouldn't, but of course we always do. This seems better than regorafenib. And yet when I look at the data, I do see a lot of adverse events; 60% of patients had some sort of grade 3 adverse event, most commonly hypertension, but also hand-foot syndrome and asthenias. So now that we have fruquintinib here, do you use this drug? How do you use it? How do you think of it in the context of regorafenib and trifluridine? Where does this one fit?
Eng: Great question. So just friendly reminder: it's FRESCO-2, because FRESCO is a separate study that was conducted in China, which was specifically for the third-line setting. That's why there's the FDA approval for third-line plus, because it was a summary of the two trials. Another clarification: It is a very selective TKI for VEGF receptors 1, 2, and 3 and not any other targets. It's a little bit different from the regorafenib.
How do I utilize it? I utilize it in the refractory setting because it has a third-line indication. I have also utilized it in certain patients who are not good candidates for TAS-102. In full disclosure, it's not just because I'm the senior PI; that doesn't make me partial to this.
I always look at all these drugs as various options for patients when we need to provide them options to improve their overall survival. I found it to be tolerated very well, and in full disclosure, I've had clinical trials that have involved this agent, and that's why I've enrolled and have had a lot of experience with this agent.
I believe it's tolerated very well. Of course, hypertension is an issue for this class of drugs; it's a class effect. But you and I both know hypertension can easily be treated if the patient is compliant with taking the medications as directed. I think it's just another great option. And now we have three oral agents that are available to patients in the refractory setting. As I mentioned earlier, for a patient who has underlying myelosuppression, this is my go-to agent. This happened to me recently, where a patient had a very low platelet count which did not allow him to participate in a clinical trial. There was no other etiology. I did not want to risk that with TAS-102, and so he was on fruquintinib. It's a single agent, and that is advantageous as well for patients who don't want to go in for the IV bevacizumab.
Schlechter: How do you sequence out the treatment of your refractory patients in standard of care, outside of a clinical trial, because not all patients have access to a clinical trial? Not all patients want a clinical trial. We often don't have clinical trials to offer in refractory colorectal cancer. So, if you're treating a patient who's had 5FU, oxaliplatin, irinotecan, monoclonal antibodies, what's first, second, and third? What sort of informs your decision-making here?
Eng: It is a discussion with the patient. I go over the side effects with them for each of the agents. In full disclosure, I probably do not choose regorafenib as my go-to for the third-line setting if the patient has a KRAS mutant tumor type or a RAS mutant tumor type. We have to think about these oral agents in the third-line setting if we don't have a clinical trial.
I discuss the schedule and the dosing and go over the potential side effects. We make the informed decision together. It's not that I just say, "Oh, I'm going to choose this for you because I was involved in the study." I don't look at it that way.
Schlechter: Excellent. And what's next? What's on the horizon? You're in the thick of it in colorectal cancer research.
Eng: Well, so are you. I'm really looking forward to some of the new agents. Obviously, we have a lot of interesting drugs in regard to the RAS mutations for codons 12C; we're moving forward with 12D development. There are pan-RAS inhibitors that are being developed. You and I were talking earlier about some CAR T studies that are being considered for phase 1.
I would just encourage all patients and providers to please refer to us at academic institutions. If you do not have a clinical trial available, please refer to us early on, in the third-line setting or fourth-line setting, if it is RAS or wild type, because we want to be able to develop that rapport with the patient and hopefully get them informed earlier on about available clinical trials. There are just a lot of interesting agents out there. The antibody-drug conjugates (ADCs) are really exciting as well. There's a lot of newer ones that are being developed in phase 1. It's a great time to be involved in colorectal cancer.
Schlechter: It does feel like we're coming up with many topics for future episodes. I hope we have some successful trials in ADCs, in RAS — in particular, pan-RAS; that would be super-cool. We'll see if we actually get there.
Today we've had Dr Cathy Eng discussing the treatment of refractory colorectal cancer. We've discussed trifluridine with tipiracil and bevacizumab; regorafenib; and the new kid on the block, fruquintinib. We've talked about the risks and benefits of trifluridine with bevacizumab; it does have an association with cytopenias. We must be cognizant of that, and we have to be careful when using bevacizumab for those patients with contraindications. We talked about regorafenib, which is an important innovation in the use of TKIs in colorectal cancer, but it does have limitations in terms of toxicity. And then the more recently approved fruquintinib which, like regorafenib, is an oral agent, and a VEGF TKI, but it's more targeted and probably has a better safety profile. Ultimately, these are patients who are best served by clinical trials, but when not available, these are good options that can be safely given with good patient education. Thank you so much for joining us. This is Dr Benjamin Schlechter for InDiscussion.
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Resources
Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer
Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colon Cancer
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Cite this: How Do You Treat Refractory Colorectal Cancer? - Medscape - Jun 05, 2024.
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