John L. Marshall, MD: We’ve got studies, we picked one on an ERK inhibitor, the HERKULES trial. Any thoughts on that approach? We had the MEK inhibitor, which improved response but not OS [overall survival] in that design. But [it did] improve response by not a negligible amount. Is the approach of beating up the different pathways all at once useful?

Cathy Eng, MD, FACP: This was a trial, at least from what I saw of the data, very early in development still, a small number of patients, 12 patients. ERK is an oral agent, it’s part of the MAP kinase pathway, and obviously we’re trying to find another option for these patients who have a poor prognosis overall. The data are very immature. There was some toxicity that was noted, and I think there was only 1 confirmed PR [partial response] out of 4 patients who were evaluated for efficacy. It’s hard to say when you only have 12 patients on a study. Obviously the pathway is of interest, and I know there were some other companies with ERK inhibitors as well, so I’ll be curious to see what happens.

John L. Marshall, MD: The world has immune therapy fever. I’m old, you all don’t even remember when there was a drug called capecitabine back a long time ago. I just said everybody should be on that, a multivitamin and a little capecitabine fixed everything. And now it’s sort of the same way with immune therapy. It feels that way. The patients want it, we sort of want to give it too, because you see these tails on the curve, and you see these people who for unexplained reasons have really remarkable benefit. And here we are again, not really with much solid scientific rationale, but let’s try it. [Going to] you Dr Cohen to start, what’s your thought about the rationale for adding IO [immunotherapy] to these BRAF combinations?

Stacey Cohen, MD: To pull us out of the rabbit hole a bit, I do want to mention that there’s a lot of overlap between BRAF and MSI [microsatellite instability]-high. I don’t think we’ve actually said it out loud, but if someone has a concurrent BRAF mutation and they are MSI-high, we recommend immunotherapy by itself without BRAF-targeted therapy.

John L. Marshall, MD: What’s your take on the counter argument that maybe they don’t respond as well and we don’t have good subgroup analysis? Do we try the IO first just because?

Stacey Cohen, MD: I usually try the IO first. We don’t know yet, but I would err on the side of that. Of course, we could look at what is the tumor mutation burden? It’s often a spectrum. We know that the higher levels seem to have greater responses, but I would give the immunotherapy before I’d give the BRAF-targeted therapy.

John L. Marshall, MD: Is that pretty much the consensus…?

Cathy Eng, MD, FACP: Oh, yes.

John L. Marshall, MD: How many inpatients do you all have right now with chronic IO toxicity in your unit? How many doctors do you have? At any one time we have a bunch, and even though with 4 out of 5, it’s fine.

Stacey Cohen, MD: To me, doublet immunotherapy gives me a lot more pause than putting them on an IO monotherapy. The response rates may be better in some patients, but then the toxicity is higher. So, I tend to use monotherapy to start out and hope that that mitigates the prospect of it. But you’re right, when it’s bad, it’s really bad. It’s something we all have to be aware of.

John L. Marshall, MD: So the argument is give them together, right? The BRAF and the IO [therapies]. We have studies that are looking at that.

Stacey Cohen, MD: It’s very interesting because it’s always about who is responding, who’s not responding, and then of those responders who stop responding, how can we induce that response and how can we [resensitize them] to that? And so, I think there are some interesting data coming out, again, immature, but we’re starting to see this idea that when patients are on BRAF inhibitors, that changes the immune environment. Maybe there is some reason why BRAF and MSI overlap anyway, but that is also shared in this situation. [With] these triple combinations now, maybe it’s not going to be the specific MEK inhibitor from before, but whether it’s another targeted therapy or immunotherapy, I think that’s going to be the next wave that we see.

John L. Marshall, MD: You guys are [part of the] NCCN [National Comprehensive Cancer Network] and you drive a lot of decision-making, do I need a randomized trial? What would be the take, if I had enough benefit [and] response rate? What would be a reason to say, because these are 9% of colon [cancer], it’s fairly rare, could I get a result that’s good enough where I get on a guideline?

Cathy Eng, MD, FACP: The MOUNTAINEER study is a prime example of a study that’s not necessarily randomized per se, but had a lot of impressive data [with] a very small subset of patients.

John L. Marshall, MD: We’re going to get to that study.

Cathy Eng, MD, FACP: That did get approved. But overall, and Stacey knows this, we don’t love nonrandomized studies for our NCI [National Cancer Institute]-sponsored trials.

John L. Marshall, MD: What if I got an 80% response rate and a 12-month disease-free survival?

Tanios Bekaii-Saab, MD, FACP: Just to separate the discussion, for MSI high….

Stacey Cohen, MD: That’s different.

Tanios Bekaii-Saab, MD, FACP: BRAF V600E, that’s a little different. Yet there is a study, SEAMARK, that’s randomizing to the PD-1, pembrolizumab, plus [encorafenib and cetuximab] vs pembrolizumab [alone] to try to see if there’s value to adding them. That does require some level of randomization because IO has such a high response rate….

John L. Marshall, MD: Well, not really. In the metastatic setting, it has about a 50%....

Tanios Bekaii-Saab, MD, FACP: No, I understand. It’s quite terrible. But I would say that for the microsatellite-stable BRAF, that’s a little different because there are a bit more of those patients. And you do need some level of randomization, and especially the early signal is promising. But if we go back to BEACON and look at the lead-in study….

John L. Marshall, MD: Really impressive.

Tanios Bekaii-Saab, MD, FACP: Exactly. With a highly selected patient population, in a small subgroup, select institutions, it looks very similar to adding the IO. Now, that’s not saying that it’s not worth looking at, and obviously there’s a study looking at that. But I would caution, because I’ve seen that unfortunately in the community and even in academic centers, I would caution adding IO plus the BEACON regimen outside of a clinical trial.

John L. Marshall, MD: That’s why I bring it up. There’s a lot of pressure on us, on our audience, from patients and patient advocacy groups to not miss IO therapy. It’s almost like everybody needs to at least try it once, either on a trial or just a Hail Mary. I worry about that.

Cathy Eng, MD, FACP: I do think, once again, for our rare patient population, we definitely want them on a clinical trial because that’s how we make a bigger impact for these patients, and this is how we get drugs approved. Going back to the study you were mentioning, SWOG 2107 is still open and that’s a 2:1 randomization.

John L. Marshall, MD: Just a quick summary of this section. If we have a known BRAF, by liquid or tissue, V600E [variation] only, forget about the other variants to BRAF for the moment. Just [in] this group, 9% or so is the running number we all use. We have an influence of first-line therapy, maybe 3 [chemotherapies] and a little leucovorin, and a biologic, VEGF. You’re not a leucovorin guy at all?

Cathy Eng, MD, FACP: I don’t use leucovorin either.

Tanios Bekaii-Saab, MD, FACP: No. But I’m going to tell you something…look at the Vanderbilt [University] experience with removing leucovorin…. You’ll see that leucovorin has been shown now in a very large data set of patients from a single institution that it doesn’t add value.

John L. Marshall, MD: It doesn’t add value.

Tanios Bekaii-Saab, MD, FACP: It doesn’t, and it makes sense. And I don’t want to spend this time on leucovorin, but it never made sense when you remove the bolus….

Aparna R. Parikh, MD: Without the bolus it never made sense.

Tanios Bekaii-Saab, MD, FACP: Sorry, this has been my thing for the last 10 years.

Cathy Eng, MD, FACP: I agree. We were on the same team, it’s been over 10 years. [We have the] same practice patterns.

Tanios Bekaii-Saab, MD, FACP: Absolutely.

John L. Marshall, MD: But for BRAF front line, we’re going to use combination chemotherapy, induction maintenance. We’re going to look to second-line doublet therapy based on these data. No need to retest as long as you know from the beginning. The MSI controversy about which one [to use] if they coexist, if it’s an MSI front line, do you give IO and then never give chemotherapy before you give your BRAF? That would be an option I think, not by the label, but certainly by the biology. Then [there are] new studies coming forward that we hope over the next year or two further enrich our discussion.

Transcript edited for clarity.