Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Axel Grothey, MD: At this point in time, in 2019, first-line treatment for metastatic colorectal cancer is still mainly chemotherapy combination plus a biological agent. And we’ve learned a lot from CALGB 80405, the large United States Intergroup-based study that compared chemotherapy backbone, either FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin] or FOLFIRI [folinic acid and irinotecan], plus either cetuximab or bevacizumab, which initially did not even have a KRAS mutation analysis incorporated in the study. But in 2008, when we learned about KRAS and later all RAS, the study was changed to really refine the patient population that we considered eligible for EGFR antibody therapy.
Only patients with KRAS wild-type tumors were included in this randomization, cetuximab versus bevacizumab. And we’ve learned actually several things. First of all, the overall study did not show a difference in survival for cetuximab- or bevacizumab-based treatment added to mainly FOLFOX in the United States. But then when we refined the analysis, did post-hoc analysis, eliminated patients with NRAS mutations and BRAF mutations, and then looked at the sidedness question—left- versus right-sided tumors—it became clear that patients with left-sided RAS or RAF wild-type tumors actually do benefit from cetuximab in terms of overall survival benefit over bevacizumab. Right now I believe that for these patients, probably 20% to 30% of patients with RAS or RAF wild-type, left-sided tumors, EGF receptor antibodies like cetuximab and panitumumab would be the standard of care.
On the other hand, we also learned that for right-sided tumors, even if they are RAS wild type, cetuximab did not work. Actually, there might even be a detrimental effect, which has influenced guidelines. For right-sided tumors and for all the mutant—meaning RAS-mutant—tumors, we definitely use bevacizumab as first-line therapy.
Now the emerging data show that we might have to look at the molecular profile of patients—HER2-positive tumors, MSI [microsatellite instability]–high, BRAF V600E–mutant cancers—and those patients might be better treated in first line with targeted approaches. That’s something that’s still being tested in ongoing clinical trials.
Fortunato Ciardiello, MD, PhD: Treatment of metastatic colorectal cancer has been changing a lot in the past 10 to 15 years. In particular, if we have to consider the role of biological agents in the first line and the role of antiangiogenic drugs and anti-EGFR drugs in the first line in combination with chemotherapy, we consider that the FIRE-3 trial has been a priority trial to illustrate that although both combinations are a very good choice for the patient, in terms of overall survival, especially for patients with ROS and RAF wild-type tumors. Especially patients whose primary tumor is located in the left colon or in the rectum, the preferred choice should be chemotherapy. In the case of the FIRE-3 trial, it was FOLFIRI, together with anti-EGFR monoclonal antibody, in this case cetuximab, because this combination was better in terms of overall survival compared with FOLFIRI plus the antiangiogenic drug, bevacizumab. From the FIRE-3 trial we can conclude that in ROS and RAF wild-type patients, a preferred option—especially if the tumor is located in the left side of the colon or in the rectum—should be FOLFIRI plus cetuximab.
FIRE-3 was a study in which patients were treated in first line with the same chemotherapy backbone, so the doublet FOLFIRI, because the FOLFIRI doublet was relatively popular in Europe compared with FOLFOX. In this case, the comparison was between FOLFIRI with bevacizumab versus FOLFIRI with cetuximab.
In terms of response, the number of responses and the deepness of response and the quality of response was higher in the FOLFIRI–plus–cetuximab arm. Whereas in terms of median progression-free survival there was no major difference between FOLFIRI plus bevacizumab or FOLFIRI plus cetuximab, in this trial. Although there was a clear advantage in overall median survival that was clinically significant in patients that received first-line FOLFIRI plus cetuximab. As I said before, this is particularly evident for those patients whose primary tumor is located in the left side of the colon. That is about 60% to 80% of patients with metastatic colorectal cancer.
Tanios Bekaii-Saab, MD: When we look at the genetic landscape or genomic landscape before we actually think about treating a patient, in my clinic I want to have RAS or BRAF, so not just KRAS. I want to have NRAS or HRAS, which is incredibly rare and may not matter as much, but if it’s there we’ll think about it. I want to have HER2 amplification, whether it’s present or not, and then BRAF mutations if there is RAS wild type. And then the sidedness will matter as well to help us decide.
If we have a left-sided tumor, I’m going to start with the 1 where there may be a little bit more of a discussion between the 2: if I have a RAS wild-type tumor that is also BRAF V600E wild type and HER2 is not amplified. And the reason why I emphasize HER2 is that we haven’t done that as much over the last few years, but more and more it has come into play in the decision-making process because HER2 amplification may indicate resistance to EGFR inhibitors. And it makes sense: they’re part of the same pathway, 1 goes up when the other 1 is suppressed, and it may drive resistance. So there’s a reason to ask why this may be happening.
Then I want to know MSI-high. And I want to know the presence or absence of an NTRK fusion, which is incredibly rare, but I think it’s worthwhile to know this from the get-go. The MSI-high is certainly important. I think for some patients, if there are no issues with reimbursement, I would actually favor, in the presence of MSI-high, starting the PD-1 [programmed cell death protein 1] inhibitor in the first line.
Let’s assume that I have a patient with a left-sided tumor, RAS wild type, BRAF wild type, HER2 amplified, MSS [microsatellite stability], and no NTRK fusion. What do I do with this patient? This is the patient when the question of EGFR versus VEGF inhibitor comes about. As I said, the data may favor the EGFR inhibitor plus chemotherapy instead of the VEGF inhibitor, bevacizumab in this case. The EGFR inhibitor could be either cetuximab or panitumumab. The problem comes from the fact that we have 2 studies: 1 from Europe, FIRE-3, and 1 from the United States, CALGB 80405. Both studies actually failed in terms of reading their intent-to-treat primary endpoint. Those were negative studies. We actually have been trying to learn from these negative studies, so caution should always be exercised when studies end up being negative and we try to draw too many conclusions from subset analyses.
But what may seem to be consistent in the 2 studies, in a lot of studies where this has been explored primarily retrospectively, is that EGFR inhibitors may have a trend. In 1 study, FIRE-3, it seems a solid trend. In CALGB 80405, it’s a small trend. Not very solid, I say, because the comparison of right versus left was not necessarily something that was preplanned. What becomes apparent is that for the patient who is willing to go through an EGFR inhibitor after discussion of the potential adverse effects of both, the marginal benefit—if any, again. Unless we randomize prospectively and solidly, it’s difficult to come up with the answer. And then that patient may receive an EGFR inhibitor.
For most patients in the United States, we still primarily proceed with a VEGF inhibitor first, and if you look at the NCCN [National Comprehensive Cancer Network] Guidelines, they reflect the lack of preference for 1 versus the other because, essentially, the data are somewhat convincing but not solid. On the right side, it’s straightforward. I just don’t use EGFR inhibitors in the first line. That’s a bevacizumab patient. For RAS mutation, BRAF mutation, HER2 amplification, I’m going to use bevacizumab in the first line. I’m not going to use an EGFR inhibitor. So really the discussion is whether, for about 20% of our patients, I’m thinking about a VEGF versus an EGFR inhibitor.