Transcript:John L. Marshall, MD: Tony, frontline, unresectable, metastatic, and RAS-mutated. What are you thinking about biologics rationale for VEGF inhibition?

Tanios Bekaii-Saab, MD: Well, this is a patient with a RAS mutation, so they automatically would not qualify for an EGFR inhibitor.

John L. Marshall, MD: Do you wait until that test comes back to make your biologic decision?

Tanios Bekaii-Saab, MD: No, I wouldn’t. Because it’s not going to change what I do for first-line. It just changes what is done in the later lines of therapy.

Cathy Eng, MD: He doesn’t live in Germany.

John L. Marshall, MD: No, Europe. It’s interesting. This is the first time we’ve ever really had an Atlantic battle over what to do in this kind of patient.

Tanios Bekaii-Saab, MD: And that battle is mostly in the RAS wild-type. Of course, with the RAS mutation, it’s more straightforward.

John L. Marshall, MD: The fluoropyrimidine—oxaliplatin or irinotecan—based on the patient in front of you.

Tanios Bekaii-Saab, MD: I typically favor irinotecan, but oxaliplatin is reasonable as well. So, either FOLFIRI or FOLFOX, plus bevacizumab. It’s straightforward.

John L. Marshall, MD: We love our FOLFOX and FOLFIRI. Has anyone here actually carried an infusion pump around their neck for 48 hours?

Cathy Eng, MD: I have not.

John L. Marshall, MD: No, you haven’t? You should do that, and we should carry pumps. Because, it’s not easy. If anybody has done home medical care for themselves or a loved one, they know it’s not. We send people home with a lot of complex gear. Anyway, these people are tough out there. Tara, RAS wild-type—I’ve got it in my bank. I know it. It’s back.

Tara E. Seery, MD: For sure.

John L. Marshall, MD: In this patient—frontline, metastatic, unresectable—what do you think with biologics and EGFR therapy?

Tara E. Seery, MD: As I said before, I’m on the FOLFIRI train. But, between panitumumab and cetuximab, they’re interchangeable. I think it goes down to your own preference of which drug you prefer to use and are more comfortable using—unless you’re in Tennessee and you have these hypersensitivity reactions. But, I’m in California, and we don’t have that. Panitumumab is every 2 weeks; cetuximab is weekly. A lot of us have been doing cetuximab every 2 weeks instead. So, they’re interchangeable. An Australian study showed that, so it’s really just preference.

John L. Marshall, MD: Are there RAS wild-type patients in whom you would use an EGFR in frontline? Clearly, you’d go in, and say, “I think you should have this one?”

Tara E. Seery, MD: Yes. I usually just tell them it’s FOLFIRI/cetuximab.

John L. Marshall, MD: In terms of that versus VEGF?

Tara E. Seery, MD: I prefer the cetuximab first-line. I think you get better data. Well, actually, there are new data coming out on Sunday. We have the abstract, and we will talk about that. Before coming out, I would always use the cetuximab first-line. I would then use the Avastin second-line.

John L. Marshall, MD: Very good. Does anybody have patients where, coming in today, there’s clearly a frontline strategy… Stroke? Are there others where there are no real comorbidity risk factors?

Daniel G. Haller, MD: Look at CALGB 80405 and even the FIRE-3 trial. The FIRE-3 trial was powered for response. Everyone expected it to be more positive for that instead of survival. In the patient, who clearly has a wild-type BRAF-mutant tumor and is symptomatic, there still is a response advantage in both studies—80405 and FIRE-3/4—with cetuximab upfront. That’s the group I typically offer it to. In patients with more indolent disease, bevacizumab tends to prolong PFS. We all want longer lives, better lives. In people who have asymptomatic disease, I’m more likely to use bevacizumab upfront, then use it in second-line, and then reserve the EGFR agent for third-line therapy.

John L. Marshall, MD: To set this discussion up, I was disappointed in FIRE-3 and 80405. These were the right people and the right drug, but we didn’t see anything. Is our biomarker not right? Are we not there yet, or is it really not that powerful of a driving mutation? Does anybody have thoughts? Could we enrich better? We’re going to talk about how we might be able to.

Cathy Eng, MD: The reality is 80405 took 10 years to finish.

John L. Marshall, MD: But it kept changing, right?

Cathy Eng, MD: Right. Because we had to amend it accordingly based upon KRAS, additional RAS analysis, etc. We really don’t have a lot of data regarding FOLFIRI, because 70% of the doctors chose FOLFOX. I think we are a little bit limited, but it’s also a big contrast to FIRE-3. Because, FIRE-3 also told you what you should provide to patients as second-line. For 80405, because we’re in the United States, everybody has every single drug available to them. So, I don’t think with the primary endpoint of overall survival, you’re going to expect to see a big difference.

Transcript Edited for Clarity