Therapeutic Strategies in Metastatic Colorectal Cancer - Episode 6

Systemic Therapy Approaches in mCRC

Transcript:John L. Marshall, MD: Let’s talk a little bit about metastatic colon cancer; unresectable, frontline approaches. Tony, I’m going to pick on you first out there in the heartland of the nation. How do you think about the choices, the menu that’s out there when making a treatment recommendation to a patient?

Tanios Bekaii-Saab, MD: The menu has become larger and larger, not necessarily better and better. It’s good as it is, and we certainly continue to try to improve upon it. The first question is, of course, what chemotherapy backbone? For the longest time, we’ve understood that we have two chemotherapy backbones that are very similar. They’re not the same, FOLFIRI and FOLFOX. They both seem to be a reasonable first approach. Then, the next question is, do biologics improve the effectiveness of chemotherapy? And the answer is mostly yes, and clearly for most.

There are two options on the menu: VEGF and EGFR inhibitors. VEGF inhibitors, at least in the first-line, there is bevacizumab. EGFR inhibitors, we have two: panitumumab and cetuximab. And then, as we started the discussion earlier, breaking down the disease from the get-go into the RAS-mutated and the RAS wild-type. And then, you have the RAS wild-type, BRAF wild-type. And what do you do with these different patients? For the RAS wild-type, you have the option of starting with a VEGF inhibitor plus chemotherapy or an EGFR inhibitor plus chemotherapy. The RAS wild-type, BRAF-mutated is a little different group. They behave very aggressively. They have a very poor prognosis. This is a patient population that may benefit from a triplet chemotherapy regimen plus/minus bevacizumab.

John L. Marshall, MD: Let me jump in. Do you know this when you’re making a frontline decision at your shop?

Tanios Bekaii-Saab, MD: Yes.

John L. Marshall, MD: Always?

Tanios Bekaii-Saab, MD: Yes.

John L. Marshall, MD: Or you won’t make it until you know?

Tanios Bekaii-Saab, MD: Well, we try to essentially have this available at the first discussion whenever possible. For most patients, it’s automatically done by our pathology department.

John L. Marshall, MD: I’ll let you finish. But others? Do you often know, or you don’t know?

Richard Kim, MD: I think that’s the problem, that for a lot of referrals from the outside, we don’t know. So if we have a patient who comes in with stage IV disease, I don’t know the RAS status, I don’t know where the specimen is, and they want to get started right away.

John L. Marshall, MD: And they want to start today.

Richard Kim, MD: Yeah, today. So I think that’s a luxury that we don’t have sometimes. So in those patients, not knowing the RAS status, I would probably use an anti-VEGF drug plus some chemotherapy backbone versus the EGFR drug. But knowing that data would be very beneficial for us to make that decision. For example, if the patient was BRAF-mutant, I agree, I would use a triplet regimen.

John L. Marshall, MD: Is there enough evidence that says if you knew it was RAS wild-type, that EGFRs are better in frontline or not? Should you wait, or does it matter, Johanna?

Johanna Bendell, MD: There’s definitely controversy there. So, we have two large studies, the FIRE-3 study and CALGB 80405, both of which tried to determine whether you should use a VEGF inhibitor or an EGFR inhibitor. Data is still totally up in the air. CALGB says no, FIRE-3 says yes. Is there a specific population of patients that may benefit from an EGFR inhibitor in the first-line? Probably yes, but I don’t know that we definitely know who those folks are yet. But I think with some of the studies that we have, that are coming, and retrospective analyses in the studies that we’ve had, we’re going to start to define some of these smaller patient populations.

John L. Marshall, MD: So do you know most of the time when you’re making that frontline decision?

Johanna Bendell, MD: Probably about 50/50. And what I’ve been coaching folks on is saying, if you don’t know it but the patient wants treatment today, first of all, a clinical trial, best way to go. If you don’t have a clinical trial, go ahead and start them on chemotherapy, but make sure that when you get that result back, it cues you in to think, oh yeah, maybe I need to change up therapy if I see certain things.

John L. Marshall, MD: Do you know or don’t know?

Charles S. Fuchs, MD, MPH: Not that I would ever take issue with something Johanna would say.

Johanna Bendell, MD: Oh wow, this is fun.

John L. Marshall, MD: That’s why I’m in between you.

Charles S. Fuchs, MD, MPH: Only because the idea of two large studies, right? I mean, there are two studies, FIRE-3 and 80405. FIRE-3 is of modest size. It wasn’t powered to look at survival; it’s supposed to look at response rate. There’s no difference in response rate between the regimens, cetuximab and bevacizumab. CALGB 80405 is a large, well-powered study which shows no difference between those two antibodies. And, as far as I’m concerned today, there is no presumed difference between these antibodies. And so, I would routinely start with bevacizumab. Why? Because I don’t always get the RAS status the day I see them, and at least the data tells us there’s probably not a difference in RAS wild-type patients.

John L. Marshall, MD: So this is an international audience that watches this. We do have this European, North American fight going on right now about this, that they see this tail separation and the like in how one interprets this. But I think sometimes we know, sometimes we don’t. I think part of the message here is that it’s controversial and you don’t have to know. Is everybody okay with that? That you have a decent frontline option even if you don’t know any molecular testing.

Johanna Bendell, MD: But if you don’t know, don’t use an EGFR inhibitor.

John L. Marshall, MD: That’s an important message. You can’t just try it and see because of harm, toxicity, all of that stuff, and extended RAS testing. Tony, I interrupted. So how do you decide? Let me just get oxaliplatin versus irinotecan. I mean, there are a lot of people who say ‘I’m an oxaliplatin guy’ and ‘I’m an irinotecan gal’. How do you decide?

Tanios Bekaii-Saab, MD: I do have my biases, certainly. I personally think that they’re relatively similar, and ultimately, with a lot of options down the line, this washes out survival in some ways. But my preference has always been to start with irinotecan in the first-line, FOLFIRI, and for a lot of reasons. Although sometimes we’re limited by the choice because of clinical trials. But the reasons are not that I think there is superiority of one versus the other. However, I find it actually easier to give and give for prolonged periods of time and easier to restart when needed. The lingering neurotoxicity can be quite problematic. In parts of the country, of course, there’s the concerns about alopecia.

John L. Marshall, MD: I have that concern.

Tanios Bekaii-Saab, MD: But the point of the matter is that the irinotecan data are actually more consistent positive data with biologics than oxaliplatin-based regimens.

John L. Marshall, MD: What are they going to get in Boston?

Charles S. Fuchs, MD, MPH: They’re going to get either one. I’d say our group is probably evenly split between FOLFOX and FOLFIRI, and I probably would say my practice is relatively split. Because as Tony alluded to, there are patients who object to the alopecia and there are patients who object to neuropathy. Because they’re relatively equivalent, you try to listen.

John L. Marshall, MD: Richard?

Richard Kim, MD: I think at our place, we use mostly an oxaliplatin-based regimen, not because I think that’s better than irinotecan, but a lot of second-line trials currently going on in the US are irinotecan-based. So if you use irinotecan up front, then you don’t give the patient an opportunity to go on a second-line trial. That’s probably one of the main reasons why I would mostly use [a] FOLFOX-based regimen up front.

John L. Marshall, MD: It’s a terrible reason, but it’s the same one I use is that with all our second-line studies, you burn them as soon you start irinotecan first-line.

Charles S. Fuchs, MD, MPH: But if you’re seeing a surgeon, which I’m sure you’ve done, I’ve done, and they say ‘I don’t want oxaliplatin,’ you give them irinotecan.

John L. Marshall, MD: Oh, yeah, no question, no question. It’s a choice.

Transcript Edited for Clarity