Application of Molecular Testing Results in Treating mCRC
Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Johanna C. Bendell, MD: I’m going to start with checking to see if your patient is BRAF mutated. How does that change your approach to treating your patient?
Zev A. Wainberg, MD: With patients who are BRAF mutated, I often put them on FOLFOXIRI [folinic acid [leucovorin], fluorouracil, oxaliplatin, irinotecan]/bevacizumab. For the people that do treat every patient with FOLFOXIRI-based regiment, it doesn’t matter whether they have a BRAF-mutation or not. Looking at the BRAF data and most of the subsets from the TRIBE study, those are the patients that clearly benefit. That is a real practical thing that I take into account when I see a patient who has BRAF mutation. I also start to get them ready for a BRAF inhibitor trial at some point. Whether it’s on trial or off, we see the National Comprehensive Cancer Network [NCCN] Guidelines now, which allow us to use vemurafenib/irinotecan/cetuximab, all of which were Scott Kopetz, MD’s, regimens that he published. You could certainly start to develop a strategy for treating patients over the next year or so.
Johanna C. Bendell, MD: The worry is that the BRAF-mutated patients have an overall poorer prognosis. Without clinical trials, we now have standards of FOLFOXIRI/bevacizumab, right, based on the TRIBE study. For second line, there is vemurafenib/cetuximab/irinotecan.
Zev A. Wainberg, MD: For BRAF, that is microsatellite stable [MSS], yes.
Johanna C. Bendell, MD: Yes, BRAF MSS. Heinz, this is beautiful science, because for BRAF V600E mutations, we have to qualify that.
Heinz-Josef Lenz, MD, FACP: Yes.
Johanna C. Bendell, MD: Colon cancers are very different from those in melanoma and sometimes other types of cancer. What’s the science behind it? Tell us about the BEACON study.
Heinz-Josef Lenz, MD, FACP: BRAF has a completely changed paradigm. We have data now with the BEACON trial to enforce this. We saw the data in Barcelona with response rate, progression-free survival, and overall survival that we have never seen in this patient population, which is 1 of the reasons why, in the United States, the BEACON treatment has moved into first line. It’s not only the choice of FOLFOXIRI/bevacizumab—there are now clinical trial options within the United States to treat them first line. Patients with BRAF mutation are the ones with significant mesenteric disease and unusual lymph node metastases; these are the ones with the cervical lymph nodes. They have brain and bone metastases, so I monitor them a little bit closer. These patients have headaches, as well. I’m not giving them Advil; I do a CT [computed tomography] scan. Knowing the prognostic features, I usually take the symptoms a bit more seriously than if it could be as just another adverse effect. As you mentioned, colon cancer is completely different from melanoma. We know BRAF inhibitors in patients who are BRAF mutated do not work because of the incredibly complex redundant signaling. You know better than I do that you need to inhibit the mitogen-activated protein kinase enzymes [MEK] downstream. You cannot do it without these 2 additional inhibitors.
What’s amazing to me is the efficacy of 3 targeted agents that have no cytotoxic efficacy, which is incredible. There are new data coming out that suggest that perhaps it should not be MEK inhibitors but extracellular signal-regulated kinase [ERK]. Maybe we should combine it with an immune checkpoint, because BRAF mutations have an interesting potential to overlap with MSI [microsatellite instability] gene expression signatures, 80% or so. We will see much more in that the field of patients who were considered bad may move into a more hopeful spectrum in the future.
Johanna C. Bendell, MD: Dirk, being in Europe, do you have access to BRAF-targeted therapy for your patients who are BRAF mutated?
Dirk Arnold, MD, PhD: It’s not registered but off-label use; however, it is done. Given the publications and published work, there are many situations in which patients can apply for this treatment that will then be paid for. I wouldn’t say it is done in many patients, but it is done with interest. To be honest, the evidence from a scientific point of view is far better than what we learn from the subgroup analyses from a randomized trial like the TRIBE trial, where FOLFOXIRI/bevacizumab came up as a standard. The evidence is clearly supporting this. It’s a prospective trial, and nearly 100 patients are being randomized to a regimen, which works nicely.
Johanna C. Bendell, MD: Heinz is alluding to BRAF-mutant concomitants with microsatellite instability. Tell us a little bit about why that’s important, and how that might change your thoughts.
Heinz-Josef Lenz, MD, FACP: We know that we have, let’s say, the overlap of these alterations, and then the question clearly comes up: Is it a patient with MSI or BRAF? This question should be given back to those who do use checkpoint inhibitors on a daily basis. I would, in theory, favor to have an anti-MSI treatment or checkpoint inhibitors in this situation. Prognostically, they’re a bit better, but not so much on difference. The prognosis will be much better if they are treated with drugs like this.