Treatment Options for BRAF V600E–Mutant Metastatic Colorectal Cancer

Centering discussion on patients with BRAF-V600E mutations in metastatic colorectal cancer, panelists reflect on the treatment armamentarium in this setting.


John L. Marshall, MD: Thank you [all] very much for that really great discussion around MRD [minimal residual disease]. Let’s drill down now on some specific molecular testing. Dr Cohen, I want you to take the lead. [Say you’ve got a new metastatic colon patient]. You have a lot of different choices of drugs, [and combinations with] 4, 3, or 2 drugs. I don’t know which drugs [to use]. How do you decide, what are you doing in frontline therapy, what molecular tests do you need to know going in?

Stacey Cohen, MD: It’s a fun time because you have so much leverage on what you do. You get to think about all of the different options. You get to have a discussion with patients. But that’s also kind of an uncomfortable space because there’s not really one right way to do it. It really comes down to guiding the discussion based on the information that you have, figuring out what other information you need, and then trying to move the plan forward.

First I’m thinking about a patient, if they’re metastatic, you’re going to have that pause and say, is this someone who’s widely metastatic, or do we even have the chance to think about this as an oligometastatic, potentially curable, potentially resectable patient, especially if it’s liver metastases only? We’re going to be thinking about this in a multidisciplinary fashion, even in stage 4. But putting that aside, if I have a more widely metastatic patient, then we’re really using molecular markers to guide our treatment. And so, as Tali had mentioned in our last segment, I am also now starting to send a liquid biopsy on the day that we meet and using a nurse navigator–driven project to actually have them order the test. …So we’re having our nurse navigators order it. We’re ordering the tissue [test] ourselves. The first thing that we really need to know [is] if they have microsatellite instability because we know that those patients should be on first-line immunotherapy.

John L. Marshall, MD: It’s almost a different disease.

Stacey Cohen, MD: Exactly. And speaking to that, in our guidelines this year, that section got moved out. We’ve stopped trying to lump it all in as 1 page on metastatic colon cancer and really recognizing that MSI-high cancer is a different disease and we need to flag that those patients absolutely need immunotherapy if it’s not contraindicated. So that’s our first step.

After that we’re looking at, do they have a KRAS mutation, NRAS, BRAF, HER2, anything else that we think might be a driver mutation? And not just do they have one of those mutations, but also what is the specific mutation? Because we are now in a time where we have the benefit of having a lot of specific inhibitors, some in standard practice, some on trial, but we really want to start to parcel off some of these rare molecular subgroups and give them therapies that probably work a lot better than our cytotoxins.

John L. Marshall, MD: Cathy, walk us down this BRAF pathway. What’s it all about? The melanoma team figured it out before we did, but we have some of this too. [Give us] a little bit about the biology, frequency, and targeting.

Cathy Eng, MD, FACP: When we mention BRAF, we’re really focused on the V600E mutation. It’s involved basically in your RAS pathway and the MAPK kinase pathway. We understand that it’s pretty rare. It’s in about less than 10% of our patient population, roughly 9%. And the fact is it is a poor prognostic indicator with regard to overall survival [OS] for our patients.

The good news is that we have a drug that we can utilize for these patients. It doesn’t work well as a single agent in colorectal cancer vs other cancers. We have to combine it with anti-EGFR therapy, and encorafenib is approved in the second line or the previously treated setting. But now we have other clinical trials that are really focused on the BRAF mutation. I think doctors are very familiar and comfortable with ordering BRAF testing now. And we encourage it obviously because that information is extremely critical to making a decision about whether or not they’re going to go on a newly diagnosed BRAF metastatic trial or are they going to just receive standard of care and proceed in the second-line setting.

John L. Marshall, MD: If you knew our molecular markers were going to be so dirty, would we have gone into colon cancer in the beginning? Maybe we’d have gone into lung [cancer] or maybe breast [cancer].

Stacey Cohen, MD: It’s a pretty dirty body part as it is. We can get away from it.

John L. Marshall, MD: I keep thinking about how you have a perfectly good marker, you block it, and all it does is go around it. It’s sort of swampy. You block one river, but it just swamps its way around. And so in almost all of the discussion we’re going to have today, we need to hit these pathways more than once. Dr Parikh, I’m going to [come to] you. You’ve done your fancy blood test, you actually have it back, ports in, ready to go, you’ve made some sort of decision. [Now] you have a BRAF-V600E [mutation]. What are you going to do now in front line for this patient if you know that going in?

Aparna R. Parikh, MD: I think there are 2 options. Option 1, standard of care. So, as [Dr Eng] mentioned, we have the approval in the second line and beyond setting.

John L. Marshall, MD: The patient’s a lawyer in downtown Boston and they want these drugs.

Aparna R. Parikh, MD: Clinical trials. There are first-line clinical trials, and we’ve started to see some of that data combining with chemotherapy with BRAF-targeting therapy in the first line.

John L. Marshall, MD: But outside of trial, what would you end up with?

Aparna R. Parikh, MD: Yes. So I think then it sort of depends on performance status, but my inclination and practice pattern has been to start with triplet therapy.

John L. Marshall, MD: Four drugs altogether? So 3 chemotherapy [drugs] and bevacizumab?

Aparna R. Parikh, MD: Yes because I was thinking FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan], bevacizumab. But you drop the bolus [dose], give growth factor, and you can get people through it just fine.

John L. Marshall, MD: Is that just in this population? I’ve been doing more of this anyway. I’ve been seeing more intensive inducers anyway.

Stacey Cohen, MD: One of my preferences.

Aparna R. Parikh, MD: Yes. Stacey and I talk about this a lot. I’m a sort of believer in triplet [therapy].

John L. Marshall, MD: Triplet?

Stacey Cohen, MD: I’ve been doing it a long time.

John L. Marshall, MD: When we say triplets, are we talking about 4 active agents?

Aparna R. Parikh, MD: Yes. I’m saying triplet chemotherapy plus your—

John L. Marshall, MD: Plus biologic of choice?

Aparna R. Parikh, MD: Not really biologic of choice.

Cathy Eng, MD, FACP: FOLFOXIRI, bevacizumab.

Aparna R. Parikh, MD: Because triplet doesn’t combine well with anti-EGFR.

John L. Marshall, MD: And that’s a smaller subgroup increasingly anyway.

Aparna R. Parikh, MD: Yes, exactly.

John L. Marshall, MD: So I’m at least in agreement with you guys. I’m up to speed on that.

Stacey Cohen, MD: It’s hard, though, because if you are trying to enroll in trials, a lot of them are FOLFIRI based and they don’t allow for prior irinotecan.

John L. Marshall, MD: Only on your second line.

Stacey Cohen, MD: Yes. In our group, we have that discussion a lot. I’m a believer in FOLFOXIRI-bevacizumab or FOLFIRINOX [leucovorin calcium, fluorouracil, irinotecan hydrochloride, oxaliplatin]-bevacizumab, as it’s now written in the guidelines, just for dosing reasons. But I think it’s a problem because a lot of trials are still very classic first-line, second-line, third-line, and our patients are not fitting into those boxes like they used to.

John L. Marshall, MD: And our [audience] might want to know, why we’re doing that? So the advantage to me- I always would cite a deeper response, there is the OS data, but at the same time, I can’t go as long. I gave up on 12 cycles a long time ago. We’re talking 6 or 8 [cycles] at most? Where are we going with it?

Aparna R. Parikh, MD: Exactly. 6 or 8 [cycles] at most, and then maintenance.

John L. Marshall, MD: Some sort of maintenance after that.

Aparna R. Parikh, MD: Yes. And then in later lines, I’m a believer in [drug] holidays.

Stacey Cohen, MD: When they progress after maintenance, sometimes I might go back to just FOLFOX or FOLFIRI. I’m not sure that we need to go back all the way up to the triplet at that point.

John L. Marshall, MD: Now you deconstruct as you readdress it.

Stacey Cohen, MD: Right. Because there you’re saying, how much neuropathy do they have? How hard was that first-line regimen? How much sticker shock do they have going back to what they remember actually experiencing before?

John L. Marshall, MD: Let’s say you do this, 6 cycles, 8 cycles, [then] maintenance therapy, maybe even a [drug holiday], and now [there is] asymptomatic progression. [Are you] going back to the chemotherapy or you go to the BRAF-V600E mutation?

Aparna R. Parikh, MD: That’s a good question. So again, it really goes back to that sort of toxicity and tolerability piece. But I feel very comfortable at that point actually moving to BRAF, and then reserving chemotherapy for post-BRAF progression.

John L. Marshall, MD: Cathy, do I need to retest? Is this one of those [times] where I need to look for if BRAF is still around?

Cathy Eng, MD, FACP: No, I do not believe you need to retest. The data support that. They’re still pretty much concordance and I would just continue.

John L. Marshall, MD: Once you got it, you got it.

Cathy Eng, MD, FACP: Yes.

John L. Marshall, MD: Anybody different?

Tanios Bekaii-Saab, MD, FACP: For any line of progression, actually, I will do another liquid biopsy.

John L. Marshall, MD: Another liquid to see if it’s still there.

Tanios Bekaii-Saab, MD, FACP: And it actually doesn’t formulate. I like the idea of alternating between chemotherapy and a biologic. That seems to address quite a bit the most resistant clone to the biologic strategy. And that has allowed us in clinic, in the absence of clinical trials, to rechallenge with chemotherapy, and to rechallenge with biologic alternating. That has given patients opportunities that otherwise they wouldn’t have. I think liquid biopsies are pretty informative. Now, they’re kind of tricky for the general practice.

Cathy Eng, MD, FACP: Do you retest for BRAF?

Tanios Bekaii-Saab, MD, FACP: No.

John L. Marshall, MD: They retest for everything.

Cathy Eng, MD, FACP: I retest at progression for other things, but not necessarily BRAF.

Tanios Bekaii-Saab, MD, FACP: With liquid biopsies I’m just looking at the clonalities, and emergence of new diseases. I wouldn’t do a tissue biopsy.

Transcript edited for clarity.

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