John L. Marshall, MD: A hard question, do EGFR drugs work in the right side? Most of our BRAF-[targeted drugs] are kind of a 60/40, 70/30 split. Now we’ve got EGFR-targeted combination therapy on these right-sided tumors. We’re seeing some swing back, one way or the other, the right side vs left side. I had to do a painful peer-to-peer [review] recently. What’s your take on that? Do you think the biology’s there?

Aparna R. Parikh, MD: Yes. I think what’s really interesting, we’ve certainly learned over the years of the prognostic differences between the sidedness. And after we saw [CALGB/SWOG] 80405 and FIRE-3 and started to understand the first-line differences of anti-EGFR therapy for the right-sided patients, the dogma has moved toward that these are patients who don’t benefit from anti-EGFR therapy. But it’s more than that I think, and there is a subset of probably right-biomarker-selected patients. I liked the paradigm biomarker analysis that was presented at ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] and is now out.

At a very high level, what they did is they looked at what was called hyper-selected patients. These were patients who lacked any of the resistance alterations that you would think would portend resistance to anti-EGFR therapy. And even with the right-sided patients, if you don’t have those biomarkers that will predict lack of benefit, the patients had benefit. So we have kept it as simple as sidedness is bad, but there are patients who I think do benefit, and it’s why I really like the patients who get liquid biopsies. So yes, in the first-line setting I don’t use anti-EGFRfor right-sided patients, but in later-line settings I will. I think there might be biomarkers, such as ctDNA [circulating tumor DNA] that can help us figure out who those patients are who may or may not benefit.

Tanios Bekaii-Saab, MD, FACP: I think Aparna hit it right on. We thought about sidedness, right vs left; we’re back to the days of the dinosaurs….But the point is, this was beautifully done and justifies the importance of getting these liquid biopsies first. Now, I’m not clear yet about how to use some of these differences between what we’re seeing in the liquid vs tissue initially. But it seems to point out that there is a subgroup of patients on the right side that benefits from EGFR inhibitors even in the first-line. And there’s a subgroup of patients on the leftside who see no benefit based on differences between the liquid and the tissue. That makes sense. The liquid is giving you a sum of all the tumors, which there’s some level of heterogeneity. For tissue, you’re just getting 1. You’re only going to get a picture of 1, which is probably accurate for 85% of the patients, but for 15%, we’re missing the bigger picture at the beginning.

John L. Marshall, MD: It relies on shedding [and] on the biology location.You’re not always getting….

Tanios Bekaii-Saab, MD, FACP: Exactly, a lot of factors. That’s why it’s challenging right now. But again, like everything else, I think we’re moving in a good direction in terms of understanding the interplay of these various mutations, alterations, [and] amplifications in colorectal cancer.

John L. Marshall, MD: As we do with all things, once we get a toehold, in this case doublet therapy in the second line for the BRAF subgroup, we try to figure out how to do it even better.

Transcript edited for clarity.