DR SOCINSKI: In 2011 we had 2 series looking at BRAF mutations in lung cancer. It was a mix of early-stage/late-stage patients.
The data suggest that it’s about in the 2% to 3% range. It’s unlike melanoma, where the dominant mutation is V600E, which is 90% or so in melanoma, in lung it’s more like 50-50. V600E is about 50%, and then non-V600E. And it’s not clear that all — whereas the V600E really are kinase-activating mutations, it’s not clear that all of the other ones are in some cases. So there’s some heterogeneity in that setting.
The data that was presented at ASCO was — many of the Lung Cancer Mutation Consortium institutions participated in. It was with dabrafenib. It was an early look at the first 20 patients. Typically, these patients had been, “heavily pretreated.” We had 3 of them treated at our institution in Pittsburgh. The confirmed response rate was 40% in that setting. That data has accrued — I’m not quite sure where the number is. Currently, it’s completed its accrual, but we don’t have an update on the response rate at this particular point. And the trial is being morphed into a second phase where, in addition to a BRAF inhibitor, there’ll be a MEK inhibitor added to that combination to kind of look at that combination in the same thing.
DR LOVE: Of course, that’s been a strategy that looks kind of promising in melanoma.
DR SOCINSKI: Right. Right. So it’ll be looked at specifically in the BRAF non-small cell population.
DR LOVE: What about the phenotypic correlations in terms of smoking and histology?
DR SOCINSKI: Yes. There doesn’t seem to be the same. It looks like the V600E is more likely to occur in the never-smoking population. The other ones seem to be more in smokers. Even — but smokers can develop the V600E. There’s some issue about — are there differences in second other mutations? There is a rate of other mutations in this population. And may that be different in smokers versus never-smokers with the BRAF, PI3 kinase, KRAS, those sorts of things.
DR LOVE: Did you mention histology?
DR SOCINSKI: For all intents and purpose, they’re all adenos for the most part. There have been some descriptive differences amongst the BRAF mutations, but nothing that there was a — I don’t think any take-home message about it that I can remember.
DR LOVE: I want to kind of go around the table real quick to see what this means to clinical practice today. But I think, John, you had a question?
DR HEYMACH: Yes. Mark mentioned something that I think is important for lung cancer. So unlike melanoma, where the story seems much more straightforward, virtually all the mutations are V600E or activating. You inhibit RAF, you get responses. So a lot of the lung cancer ones are actually inactivating. So the Y472C mutation, for example, is inactivating. And so there have been reports of responses in activating mutations, inhibiting another of the pathways. So we had one from MD Anderson by Faye Johnson where the patient was treated with dasatinib, which we think of as a Src inhibitor, and actually had a complete response that lasted 3 or 4 years. And it turns out that when you inactivate BRAF, you actually activate some other downstream pathways that are targets of the drug.
So there’s a nationwide study for dasatinib for the inactivating BRAF mutation. So I think for BRAF the story’s going to be more complicated.
DR LOVE: What I want to figure out is what are you doing right now, for example. So let me just again see if I can kind of poll you. I’ll start with Chandra. In what situations, if any, do you do BRAF testing? And in what situations, if any, would you try to access a BRAF inhibitor that’s approved? Which one? And what kind of obstacles are there to actually getting it? Simple question.
DR BELANI: So if you go to the last question first, there are very many obstacles outside of a clinical trial to access a BRAF inhibitor, because it’s not FDA approved and not paid for. So it is good to get the patient into a clinical trial where available. So I’d send them to Greg Riely to put them on the trial at Memorial. It’s not too far from my place.
DR LOVE: What’s your trial?
DR RIELY: So the dabrafenib trial we have.
DR LOVE: Dabrafenib. And the patient says, “It’s on the market. Can’t you just give it to me? I don’t have to go to New York.”
DR BELANI: So that’s why if the patient is willing to agree to pay for the drug, then I guess that’s a possibility. And I haven’t had a patient who has agreed to pay for the drug.
DR LOVE: And who would you test and at what point?
DR BELANI: So at this point in time we are testing all adenocarcinomas at the institution, we are testing the SNaPshot or Sequenom. We’re testing BRAF as part of that testing.
DR LOVE: And if the patient were to say, again, “I’d really like to be treated off study,” which of the 2 approved BRAF inhibitors, dabrafenib or vemurafenib, would you select?
DR BELANI: So far, if they are V600E mutations, the data is there based on the trial with dabrafenib. Vemurafenib is only anecdotal data in lung cancer.
DR LOVE: And would you use the specific type of mutation to decide whether or not to do this?
DR BELANI: That’s — we do get these inactivating mutations of BRAF when you do the next-generation sequencing or when we send out our tissue to Foundation Medicine.
So in that case, I have not had anybody who has had that mutation. We have had DDR2 mutations with squamous cell who have been treated with dasatinib. But we do not have a clinical trial or access to a clinical trial for —
DR HEYMACH: In fact, that same trial has both DDR2 mutations and inactivating BRAF mutations on it that you mentioned.
DR LOVE: So I’ll pose the same 18-part question to you, Dave, as a second opinion. Do you agree or disagree?
DR SPIGEL: So hold on. I think it’s a pretty remarkable study and I was talking with some folks earlier. I think it was probably, in my opinion, the best thing to come out of ASCO in lung cancer. And it was not even in the lung cancer section, if you guys remember. It was in kind of a molecular section and there were 2 papers presented, but it wasn’t one of the major oral lung sessions.
I think it’s quite remarkable. And my understanding is that this could be the beginning of changing how we practice lung cancer care very soon, in the next year, potentially. So this trial, my understanding, has 40 patients on it right now. And that could be enough to file with a drug like this, with response rates like that. And that could change how we practice. It may not be long before BRAF testing is actually in the same space as ALK and EGFR testing as a standard recommendation. If a waterfall plot and — there were 2 patients out well over a year on that study who were heavily pretreated.
That could be enough to get a drug like dabrafenib approved. That could change the way we practice. Right now, I think there’s no role in BRAF testing outside of a clinical trial. Yes, we do it at our center. And I’ll tell you, one of my partners in 1 month had 2 patients with BRAF mutations discovered. And then we have a third one discovered the next month, not V600E mutations.
DR LOVE: You guys, or you won’t use it off study?
DR SPIGEL: So I have not. We have trials. So it’s been easier to steer patients to those studies with newer agents. We actually have — it’s a terrible name for a trial. A lot refer to these wastebasket trials, where approved agents are available. So we have a trial where it has multiple arms, where vemurafenib, a drug approved in V600-mutated melanoma, is available for any other tumor type that has a V600E mutation. So a patient could get vemurafenib that way.
DR HEYMACH: We don’t call them wastebasket, just basket.
DR SPIGEL: It’s just basket. Just basket.
DR LOVE: So a doc in a rural location who has a patient who really can’t travel says to you, “What about using a BRAF inhibitor off study, if I can get it, or if I can get it paid for?”
DR SPIGEL: I think if the options are — if this patient is refractory and you’re looking at docetaxel or gemcitabine or vinorelbine, absolutely.
DR LOVE: And if it’s a patient who has metastatic disease, but not that much and not that critical a location and they’re really asymptomatic and they’re pretty intelligent — maybe they’re a doc — and says —
DR SPIGEL: They’re always a doctor.
DR LOVE: “How about it? How about if I start out – I’ve got this BRAF mutation. How about if I start out on a BRAF inhibitor and then I’ll take my chemo, if I get worse”?
DR SPIGEL: I think a patient like that, that’s well informed, that certainly understands the risks and benefits, what they’re kind of passing up, so to speak, I think that’s reasonable. We all have to remember the downside of presuming things, so that — erlotinib would work in somebody you think has an EGFR mutation, where it’s clearly a detrimental path for that patient.
DR LOVE: One thing I’ve got to say — and I think general oncologists would say this to you, probably, after their experience in melanoma – is, “Be careful.”
DR BELANI: Yes.
DR LOVE: And what I’ve heard about is be careful about sunburn, in particular. I guess that’s more of an issue with vemurafenib, but —
DR SPIGEL: Yes, and the squamous cancers.
DR LOVE: And, of course, the secondary squamous cancers.
DR SPIGEL: Yes.
DR LOVE: So it is a different kind of spectrum of problems, but they’re not completely innocuous drugs and have to be given with care. But again, I think the oncologists in practice already know that from melanoma.