Tanios Bekaii-Saab, MD, FACP:Today, it’s a little different world than, let’s say, a year and a half ago where mutational status was the only important thing for us to decide on VEGF versus EGFR inhibitors. Today, in addition to molecular characterizationand I’ll quickly refer to what that means—we also have anatomic considerations. There are also, of course, other concentrations: performance status, age, and microsatellite status. So, we’re really now thinking about colon cancer in the patient who presents to us in terms of deciding on what therapy we should proceed forward with, with decisions that are linked to molecular/genetic characterization. So, it’s very important to have an expandedRASnotKRASwhich includes expandedKRAS, expandedNRAS.
And also, I think it’s very important to getBRAF, becauseBRAFhelps us a lot to understand how aggressive the tumor is and even consider 3-drug versus 2-drug therapy plus bevacizumab. Microsatellite status is very important. Everyone should get microsatellite status checked. If the patient is MSI-high, then you can consider immune therapy or an immune therapy clinical trial.
And then, there are anatomical locations. So, this now goes into the equation, regardless of theRASstatus. Let’s say you have a patient like this one who’sRASwild-type,RAFwild-type,BRAFwild-type, and microsatellite stable, but the tumor is on the right side. Those patients do not seem to benefit from EGFR inhibitors. So, anatomic location mattersalthough conceptually, let’s say 2 years ago, we think ofRASwild-type and you have the 2 options. Well, today, if you’re on the left side of the colon, you have both options. We can talk a little bit more about this. But on the right side, clearly in the first-line setting, EGFR inhibitors do not seem to have any benefit. And so, those patients, regardless of theRASstatusbecause of the anatomic location on the right—should receive bevacizumab plus chemotherapy, if eligible, first.
On the left side, it gets a little bit more complicated, in a good way, because then we have more options. All the studies that we have on handlike CALGB/SWOG 80405—are, of course, relevant to our practices in the United States, but we also have hints from other studies. There’s the European study, FIRE3, which is primarily powered for response rate. CALGB was primarily powered for survival and reflects more the practice in the United States.
The 2 studies sticking together suggest that an EGFR inhibitor may have a little edge on the left side. But when you look at the overall picture, you continue to integrate into the equation potential toxicities, you have to think about your biologics. EGFR inhibitors can cause a rash and can enhance the risk of diarrhea with chemotherapy. When I give bevacizumab, I say it has more silent toxicities.
So, when you look at the NCCN guidelines today and the way they included the right versus left story, then it’s clear that for theRASwild-type tumors, EGFR inhibitors in the first-line setting are not recommended. On the other hand, for the left side, both EGFR and VEGF work. So, bevacizumab, cetuximab and panitumumab are indicated in theRASwild-type. Now, of course if you have aRASmutation tumor, then it’s a no-brainer; it’s bevacizumab as your only biologic whether you’re on the right or the left, and that’s in the first-line.
Now when we start thinking about going down the line of therapywe’ll talk a little bit more about that later—things may get a little bit different in terms of our thinking, because we start running out of options as we go down the line of therapy. But your first-line of therapy is essentially the most important line of therapy because it sets the stage for everything you do in second-line, third-line, and beyond, and it’s also the line of therapy where patients spend most of their remaining lifetime on therapy. It’s very important to make the right decision in first-line in terms of what biologic, based on molecular characterization, genetic characterization, as well as anatomic characterization, and after that, of course, other clinical factors.
Transcript edited for clarity.