EGFR Therapy in Left-Sided CRC

Transcript: John L. Marshall, MD: Tony, talk a little bit about right versus left-sided tumors, and this really transforming thinking we’re having to deal with, with this new knowledge about right versus left, and how that influences your molecular testing. Do you behave differently if it’s a right-sided versus a left-sided tumor?

Tanios S. Bekaii-Saab, MD: Not much, in the first-line at least. And that brings the point that Chris and others have brought as well. Unlike lung cancer, we don’t have positive predictive biomarkers, we only have negative for the most, except for MSI-high, which can be done in a couple of days. So, the question is, does it really make a difference for me immediately, in terms of choosing therapy?

So, we know that right-sided tumors, even in the presence of RAS wild-type, BRAF wild-type, genotype, do not respond to EGFR inhibitors. Now if EGFR inhibitors were part of your first-line armamentarium, that certainly would matter. But for those where it doesn’t, it doesn’t really matter. Now it becomes very important as you start thinking about sequencing strategies.

For the left, arguably it’s a little bit different in terms of the line of thinking. There’s a little hint of data that suggest that perhaps left-sided tumors may do better with EGFR inhibitors. And it’s a little bit better at least.

John L. Marshall, MD: Should we be ignoring this little, little bit better? We keep saying it’s a little bit better. So, I want to kind of pick on everybody.

Tanios S. Bekaii-Saab, MD: Well, it depends on what side of the ocean, Atlantic Ocean, you’re on. When you look at the curves from the study, from CALGB 80405, there’s a little bit of separation. The problem is, of course, that that study had been ongoing for quite a while, for 10-plus years. A lot of standards changed in the meanwhile. So, we don’t know if that effect is just related to the EGFR inhibitor itself on the left side in a RAS, BRAF wild-type, etcetera, tumor.

So, as we refine it further and further, the curves separate just a little bit more, but you still don’t see enough of a separation to subject, I think, patients to EGFR inhibitors in the first-line setting, when they spend most of their life in the metastatic setting on treatment.

John L. Marshall, MD: Let me be provocative. Let me set a case up where it’s a 40-year-old, bulky disease, symptomatic, front-line, left-sided, all wild type—RAS, BRAF, everything else. The tumor is in place and narrow. All right? So, their bowels are moving but they’re narrow. To me you’ve got 2 choices. You’re going to do a FOLFIRINOX/BEV kind of approach, and you want a response. Or you’re going to do EGFR frontline therapy.

Chris, you get to go. What are you giving this 40-year-old?

Christopher Lieu, MD: I think if you’re looking for a true response, and so on a patient that’s young, healthy, fit, but symptomatic, and you want that response so that the patient literally has less pain, I think I would typically go with a FOLFIRINOX or a FOLFOXIRI/BEV regimen because of the increase of about 10% of response rate. I think that is a little bit more validated than maybe starting with an EGFR inhibitor, though I do think it’s an option. If a patient is able to take that triplet therapy, then we would do triplet chemotherapy with bevacizumab.

John L. Marshall, MD: Joleen?

Joleen M. Hubbard, MD: I actually am a believer in doing the EGFR inhibitor upfront for left-side tumors. Plus, if it’s a narrow tumor and the patient may have an obstruction risk, then you don’t have that contraindication with bevacizumab onboard. I think 39 months for the subset of the group in the 80405 study that had the EGFR inhibitor upfront, left-sided tumor, I believe that data and I would definitely give an EGFR inhibitor upfront. I think the skin toxicities are concerning. But I think if you really are aggressive and you work with a dermatologist, you can manage those.

John L. Marshall, MD: Now this is only about 20% of the total population we’re talking about, and then a subset of those. So, this is not a common scenario, I would say. But I actually say I’m starting more and more to vote with Joleen. Howard, your vote?

Howard S. Hochster, MD, FACP: Well I did a study with biweekly CAPEOX and cetuximab about 15 years ago, and there was a lot of skin toxicity—acute skin toxicity. And then the chronic one, where you start getting cracks in your fingers. I had some patients that didn’t care how much rash they got, but once it affected their golf game, they were really annoyed. But I don’t really think it’s more effective than giving FOLFOXIRI.

So, I think the triplet really is what gets you the response. And I think it is difficult for a lot of patients once you’re starting to add in the toxicity of the EGFR antibodies with the cutaneous toxicity. But, I will say that we are going to have a study soon looking at FOLFOXIRI plus panitumumab for left-sided RAS wild-type patients. So, this guy would be perfect for the study we’re going to do to really see how much better it is. We’re expecting the response rate to be like 90%, otherwise it’s probably not worth it.

John L. Marshall, MD: Did I get your vote?

Tanios S. Bekaii-Saab, MD: Well, so let me put this back into perspective. You’re asking for a response. As Chris mentioned, we know that with FOLFOXIRI/bevacizumab you get added response. The FIRE-3 study was powered for response, and it looked at an EGFR inhibitor versus a VEGF inhibitor, cetuximab versus bevacizumab. In the initial analysis, actually there was not much difference between the response rates. So, I’m not buying this, “I get more response with an EGFR inhibitor.”

John L. Marshall, MD: I think it’s similar though.

Tanios S. Bekaii-Saab, MD: I don’t even think so. I think FOLFOXIRI probably wins. Here’s the beauty about using a FOLFOXIRI/bevacizumab versus an EGFR inhibitor, and this is when I think about my patients, I don’t think just about what I see in the first line. I’m thinking about the lifetime. FOLFOXIRI/bevacizumab, I can actually tone it down to a maintenance strategy that has some proven value, and we’ll talk about this in a little bit. With the EGFR inhibitors, I still have no study, no good study at least, that tells me how to maintain those patients.

John L. Marshall, MD: It is a struggle.

Tanios S. Bekaii-Saab, MD: So overall, I’m thinking, yeah, you know, maybe a month or 2 here or there, and I think they’re important, but, in the overall strategy, I think this would make more sense. But, again, I would say that they’re equally reasonable.

Transcript Edited for Clarity