John L. Marshall, MD: So let’s shift gears for just a little bit. I am by far, I think, the oldest member of this panel and remember well the evolution of targeted therapy in colorectal cancer. And when it first came out, if we remember back to cetuximab’s initial approval, it was with a United States study named BOND-1. And this was in irinotecan-refractory patients who got either cetuximab alone or continued the irinotecan beyond progression, if you will, and that doublet performed pretty well.

And then very quickly we in the United States—I think Lynn Saltz was the principal investigator—did BOND-2, because we’re not even smart enough in America to rename a study, we just went and called it number 2. And then we added a VEGF, in that case bevacizumab, showing another positive result.

And I have to tell you, a lot of us jumped on this bandwagon and said this was a good idea, we were using it, and then panitumumab studies were done in frontline looking at the combination. Now remember, this was before we knew anything about right and left and RAS and all that stuff, and those studies were dead negative. And we went from an excitement of combination biologics to a dead stop—that we were no longer to do that guideline, shut it down, and this is an evil, biologically wrong thing to do.

Howard Hochster is presenting at this year’s meeting a Cooperative Group study looking at this again, if you will, the same basic model. Now at least enriched for KRAS, not right and left. Anybody got some thoughts on this clinical trial? Bert, what do you think?

Bert H. O’Neil, MD: Well, I haven’t yet seen the entire data set, but we gather that adding ramucirumab to the backbone of irinotecan and cetuximab actually appears to improve, at least, progression-free survival in the second-line setting. So I think at the moment we can conclude there’s not an obvious detriment. I don’t yet know how impressive looking the benefit is. The patients did well overall. We know that for both arms, the overall survival from start of second line is about 20 months, which is a lot bigger than the same number back in the BOND days.

John L. Marshall, MD: One of you people must be on NCCN [the National Comprehensive Cancer Network]. What does it take to get on NCCN? Sometimes you can just get approval for like 12 people who had a good day, and then you’re on the guidelines. Sometimes a big phase III study with a P-value and the NCCN say, “No, that doesn’t count.” If these data hold up, and we’re seeing some benefit in a Cooperative Group run, randomized trial, do you think this would tweak practice patterns at all?

Wells A. Messersmith, MD, FACP: I hope not. So it’s a small trial. It’s only 100 patients, it’s a phase II. I think it’s a hypothesis-generating trial. And in a way, to me, one of the themes of this meeting, which we’re not seeing any sort of blockbuster new drugs, is these sort of incremental benefits from maybe resequencing things. What do we use first? What do we use second? Are there biologic differences when you use one versus another? Do tumor cells have adaptive responses that make them more or less susceptible to certain therapies? That is, I think, a thematic aspect of this meeting. So the question becomes in the second-line setting, is this suddenly a valid approach? The trial is positive for PFS. I think it’s sort of hypothesis generating. It should not change practice. I hope that no one goes home from this meeting and starts using double biologics in the second-line setting because remember …

John L. Marshall, MD: So I should cancel that order then?

Wells A. Messersmith, MD, FACP: You should cancel that order, yes. Exactly. Your NCCN membership has been rescinded.

John L. Marshall, MD: You all won’t let me in that group anyway.

Wells A. Messersmith, MD, FACP: So I think another interesting question is, should we go back and restudy this? I think that will be one of the things that we’ll have to figure out. Should we do a large study? Is a large study worthwhile?

John L. Marshall, MD: Or increase the enrichment. You know, understand more about it.

Transcript Edited for Clarity