Insights From: D. Ross Camidge, MD, University of Colorado Cancer Center; John L. Marshall, MD, Georgetown University; Hussein A. Tawbi, MD, PhD, University of Texas MD Anderson Cancer Center
John L. Marshall, MD: Right now, most of us are doing molecular profiling on our metastatic colon cancer patients right from the beginning. We want to know MSI [microsatellite instability]. We have to know RAS. Now we have to know BRAF, and we need to know HER2. So we need to know all of these things to make treatment choices.
But let’s say you’ve done that, and now you have a RAS wild-type but BRAF V600E mutation in your patient. What do you do? When do you use these other therapies? There is, in fact, a frontline study going on right now that is looking to try and see if targeting BRAF right from the beginning will carry the day. But I think our current standard would be to probably follow a pretty similar path to what most of us have done. We’d start with some sort of combination chemotherapy, a FOLFOX [folinic acid/fluorouracil/oxaliplatin], FOLFIRI [folinic acid/fluorouracil/irinotecan], probably bevacizumab in the frontline, as we’re used to doing.
Where it gets tricky is, now what? We have to remember that BRAF tumors are more aggressive. We might have given FOLFIRINOX [folinic acid/fluorouracil/irinotecan/oxaliplatin]/bevacizumab in the frontline, because we know that these tumors are more aggressive. Usually in the second line, for a patient with a BRAF V600E mutation, I probably would go to this combination therapy. That’s probably when I would play that card, unless for whatever reason, I’ve got a very quiet tumor. These regimens are pretty well tolerated, but they are not without toxicity. They do have some issues. So having this abnormality, I would probably use this triplet combination in the second-line setting.
We also have to remember that often, when you have BRAF mutations, you also are MSI-high. So we’ll have to discuss that with our patients. We’ll have to decide for ourselves, do we try immunotherapy first, or do we try BRAF targeting? I would lean more toward the immunotherapy approach first. When it works, it works really well; and it can work for a very long period. We have much less experience so far with these BRAF triplet combinations.
We are all aware of the toxicities of EGFR therapy, right? You have the skin rash, and you have to worry about hypomagnesemia, some diarrhea, and those sort of things. And when we first started combining these BRAF inhibitors and MEK inhibitors, we were seeing some additional toxicity—fatigue, more skin rash. But actually, in the BEACON study, a fairly big randomized trial comparing traditional chemotherapy approaches to these targeted regimens, we actually don’t see that much toxicity. The rate of grade 3/4 toxicity is relatively low, and looks to be pretty manageable. I think all of us are just beginning to gain experience with the regimen. I’m more or less dosing it the way it says in the study. But as with everything, we’ll figure out how to manage that as we go along. However, it’s not an overwhelming toxicity. It is manageable, but it’s still very important to coach your patients through on skin rash and other adverse effects.
We’re increasingly giving oral treatments to our patients. We write these prescriptions, they go to specialty pharmacies, they arrive, and we spend a lot of time helping support the patient in obtaining the medicines. But we also have to remember that we have to ensure and support them through compliance. These regimens require following the rules. It’s not as simple as waking up in the morning and taking your blood pressure medicine. You’ve got to track it. And so, use your team to coach patients. Follow compliance. Follow up. See them in clinic. Check on them. Check their laboratory results. Make sure that they’re doing the treatment properly.
One of the tricks I always like to use and the question I like to use is, “So, remind me again, how are you taking your medicine?” And they say, “Well, you know.” And I’m like, “No, I want you to tell me.” I’ll even joke and say, “This is a quiz.” So that really is one of those steps that I think is important for us, to make sure our patients are doing the right thing.