DR HECHT: BRAF mutations are about 10% of all colorectal cancer. However, actually, BRAF is context specific. So, BRAF in a patient who has metastatic colon cancer, those people do poorly. But actually overall, though, it’s not necessarily that way in people who don’t have metastatic disease because only about 3% of patients with metastatic disease have a BRAF mutation, if you understand what I’m saying. So whether someone has metastatic disease as opposed to Stage II or Stage III, there’s definitely a context dependency that’s really not totally clear.

DR LOVE: And in a way, that applies to MSI, too, doesn’t it, because in the adjuvant setting, they do well, Stage II?

DR HECHT: Yes. And there’s an overlap, because, remember, MSI is also associated with BRAF in patients who have sporadic.

DR LOVE: Right. Can you go back through that again?

DR HECHT: Patients who have MSI, there are two groups. There are those patients who have an inherited predisposition, which is Lynch syndrome. And then they have a germline mutation in one of the DNA mismatch repair genes or EPCAM.

Then there are the sporadics. And the sporadics basically turn off one of these genes by other mechanisms. They tend to be epigenetic mechanisms. In patients who have MSI, you get the pathology report and it comes up and it says, “MSI” and — at least at UCLA and many other places — they do reflex BRAF testing because if the patient’s tumor is BRAF mutant, it is sporadic. It is not Lynch syndrome. Therefore, we don’t go down the genetic testing route and to the genetics counselor looking for other things. That goes off to the side, saying, “This is sporadic disease.”

DR LOVE: And are they linked? Is there a higher incidence of BRAF in MSI patients?

DR HECHT: Yes. But just remember, we’re talking people who were originally diagnosed. As a matter of fact, the problem with BRAF mutation in metastatic disease is that these patients tend to do poorly. And there’s also some biological differences between colorectal cancer and melanoma. Of course, BRAF, we think about the same V600E mutations. That’s the classic canonical mutation that you see in melanoma.

And, in fact, once again, we’re not trailing lung cancer. We’re trailing melanoma in colorectal cancer because there are drugs that have been developed to inhibit BRAF and, also, further downstream, MEK. And these drugs have been effective, though not effective long enough because they tend to have resistance that occurs fairly early. But they certainly help patients with melanoma, and these drugs are out there.

There are differences. For example, vemurafenib, the anti-BRAF, before its approval, we were part of a trial. Scott Kopetz eventually presented that and published it. It took them a long time to publish it.

We screened about 100 patients to get 20 patients who had BRAF mutations. And this was in 5 institutions around the world. And we had 1 response that was short-lived. So it is different than melanoma.

So then, when you do that, people went back to the biology. And it turns out that there are feedback loops that you can see not just in colorectal models, like in cell lines, that don’t really seem to be there for melanoma cell lines. So you need to hit probably above and possibly below at the same time. Vemurafenib by itself doesn’t work.

There have been several trials that either have been done or are now just completed — a larger cooperative group trial — in combinations. And the combinations are generally in combination with an anti-EGFR, so upstream, together with a BRAF inhibitor. Some of them are downstream, and some of them are with chemotherapy, generally with irinotecan. Unlike single agent, these clearly have activity. And probably 20% to 30% benefit.

DR LOVE: So, again, just getting down to what you do in your own practice outside a trial setting in terms of up-front treatment of metastatic disease that’s BRAF-positive, what do you do?

DR HECHT: So, remember, I said they tend to do poorly. There is data that Americans tend to ignore from the Italians of all three drugs together, FOLFOXIRI. And Falcone and that group have been doing that for a long time because we were so entranced with biological agents while they, at the same time, were putting all these drugs together. And what they saw was, not surprisingly, a higher response rate.

But there have been several trials, both chemotherapy alone and together with bevacizumab, where triplets seem to do better than doublets. Not surprisingly, the toxicity is somewhat higher.

It looks like about 30% of people fall off between first-line and second-line therapy. And maybe you’re picking up those people. In retrospective looks at that 3-drug combination versus 2-drug combination, the numbers are small. But the BRAF-mutant patients, this bad group of patients, tended to do significantly better on the FOLFOXIRI. So that’s why people are using that combination.

Metastatic wild-type nonsquamous non-small cell lung cancer (NSCLC)

Metastatic colorectal cancer (mCRC)

Metastatic epithelial ovarian cancer (OC)