Key Takeaways in the Treatment of Advanced Colorectal Cancer - Episode 4
Tanios S. Bekaii-Saab, MD: In addition to the molecular and genetic markers, right versus left is an important biomarker. It’s an anatomic biomarker if I may call it as such because it really relates to sidedness and tells us whether certain agents work in certain patients or not. Let’s take, for example, the right-sided colon. The right-sided colon seems to confer resistance, just the sidedness itself, to EGFR inhibitors, at least in the first line. For a right-sided colon cancer that is RAS wild-type, BRAF wild-type, HER2 nonamplified—all the elements that seem to predict positively for response to EGFR inhibitors—when you introduce the sidedness on the right, these agents show very little activity, if any, on the right side.
As such, if a patient comes to you with a right-sided tumor, the first line of treatment or the first option would be bevacizumab. When the patient progresses through the first line of therapy and goes to the second line, the question is, do you now introduce an EGFR inhibitor? And the answer is, in my viewpoint, no. I think those patients will not respond well to an EGFR inhibitor.
In fact, 1 of the concerns I have from the CALGB 80405 study is there may be actually a negative trend, meaning a detrimental trend for applying EGFR inhibitors in this. I will go even more controversial. When you go to third line, I will still not introduce, at that point, an EGFR inhibitor, and understanding that the REVERCE trial, which was primarily conducted in Japan, did seem to favor regorafenib given before cetuximab rather than the other sequence, regardless of left versus right. Although in my clinic, I apply that principle mostly to the right side. Those patients will go through chemo [chemotherapy]—bev [bevacizumab], chemo–bev [bevacizumab], regorafenib, then maybe even TAS-102 [trifluridine, tipiracil hydrochloride] before an EGFR inhibitor. EGFR inhibitors will come definitely after regorafenib, and in some patients even perhaps push them beyond TAS-102 [trifluridine, tipiracil hydrochloride]. That’s on the right side.
I think 1 important aspect of what we do is that for the longest time, we’ve always understood that there is benefit to continue antiangiogenic agents beyond first line, in fact from first to second line. Regorafenib hits a little bit of VEGF. It’s not primarily a VEGF inhibitor, so I’m not sure about the value of the VEGF inhibition piece itself beyond second line. That said, we have 3 agents that target VEGF in different ways. Bevacizumab targets the ligand, ramucirumab, the receptor, and then ziv-aflibercept essentially acts as a decoy and captures all the ligands away from the receptor.
Is there an advantage to using 1 versus the other? The answer is absolutely none. Historically, they all seem to perform the same in second line. Ziv-aflibercept is a little more toxic. Ramucirumab is more expensive, and frankly none of those seems to confer a better advantage versus bevacizumab. Therefore, in my practice, if I choose to go with a VEGF inhibitor beyond first line, it’s usually bevacizumab, so continuation of bevacizumab. We do not switch to ramucirumab or ziv-aflibercept.
Transcript Edited for Clarity