MCRC: Sequencing Based on RAS Status and Tumor Sidedness

Transcript: Scott Kopetz, MD, PhD: When a patient has progressed on first-line chemotherapy, the discussion about options for second-line therapy depend on a number of different factors. For a patient who has a KRAS- or NRAS-mutated tumor, the second-line therapies are really using the alternate cytotoxic therapy, switching from FOLFOX [folinic acid, fluorouracil, oxaliplatin] to FOLFIRI [folinic acid, fluorouracil, irinotecan] or vice versa, and then continuing bevacizumab in my practice. There are certainly datasets talking about alternate antiangiogenic therapies. There’s aflibercept or ramucirumab in combination with FOLFIRI in this setting, although there have not been any head-to-head comparisons of those approaches with bevacizumab. There are some subtle differences in toxicities with these different regimens. But I think the practice pattern in the United States currently is to continue the bevacizumab based on the TML study demonstrating an overall survival [OS] advantage for this approach.

Conversely, for a patient who has RAS/RAF wild-type disease, especially those with left-sided disease, most of those patients in my practice will receive EGFR inhibitor in the first-line, in which case second-line therapies include the alternate cytotoxic and bevacizumab. However, if a patient did not receive an anti-EGFR therapy in the first line and instead received bevacizumab, I find that the second line is a good time to combine the anti-EGFR therapy with a chemotherapy backbone.

There are certain scenarios where based on the molecular profile, we’re doing something different. For example, for a patient with MSI [microsatellite instability], if they haven’t received a PD-1 [programmed cell death protein 1] inhibitor already, they go on to receive a PD-1 inhibitor. For BRAF-mutated V600E disease, those patients would go on to receive a BRAF-targeted therapy. And it’s also an opportunity to intervene based on NCCN [National Comprehensive Cancer Network] Guidelines with a HER2-directed therapy for HER2-amplified disease.

Richard Kim, MD: In patients with right-sided tumors who are RAS wild-type, based on the post hoc analysis of three large phase III studies, we know that there’s no benefit of adding EGFR inhibitors to chemotherapy in right-sided tumors. So, clearly, if a patient has a right-sided tumor, the patient will get a chemotherapy plus bevacizumab backbone in the first line. The biggest question that comes up is, what happens if those patients progress in the first line? Should you ever bring in an EGFR inhibitor in a RAS wild-type patient with a right-sided tumor. And I think that’s a question that has still yet to be answered. Are there some data? Yes, there are some data. As you know, there are many trials done in the second-line setting comparing an EGFR inhibitor to an anti-VEGF inhibitor. The problem is that they didn’t collect the left- versus right-sided information. Therefore, the data are not clear.

But there’s a trial called the COMET study that was presented a couple years ago. This was a randomized study in patients, where everybody got FOLFIRI plus bevacizumab then they were randomized to either FOLFOX followed by irinotecan and cetuximab, or vice versa. Obviously, these are the patients who are KRAS wild type. And, in that study, the primary end point is overall survival. And they also looked at the right- versus left-sided tumors. And what they found was that in the patients with the right-sided tumor, the patients who got FOLFOX second line and got EGFR third line, there was an OS benefit of close to couple months, telling us that in the patient with a RAS wild-type right-sided tumor, EGFR may be better used in the third-line setting.

Then there was another trial called the REVERSE study. This was a trial that has been published and was presented last year. This was a trial done in Japan where patients failed standard chemotherapy, then they were randomized to either regorafenib followed by cetuximab or vice versa in patients with KRAS wild-type disease. And, in this study, the primary endpoint was overall survival. And it showed that patients who got regorafenib first followed by cetuximab had an OS benefit. But, when they looked at the left- versus the right-sided tumors, there was no difference, once again telling us that maybe getting an EGFR inhibitor third- or fourth-line therapy would be more beneficial than earlier on.

The last study that I want to point out is that there was a randomized phase III study that compared cetuximab with best supportive care. This was a pivotal study that got this drug approved. They went back and they collected some data regarding the right- versus left-sided tumors. In that study, when they looked at the right-sided tumors and compared cetuximab versus best supportive care, there was a slight improvement overall survival, favoring the arm of cetuximab in the third-line setting.

So, if you take all that into consideration, it seems like there is maybe some modest activity of EGFR inhibitors in right-sided tumors. Based on some of the data of the REVERSE study and COMET study, I probably would not use it in the second line. However, in the third- and fourth-line settings, if I don’t have any other options available, that’s something I would consider. But definitely I would wait until the third or fourth line before I use an EGFR inhibitor in a right-sided tumor that is RAS wild type.

Scott Kopetz, MD, PhD: There’s interest in trying to improve the use of anti-EGFR therapy for patient benefits in later lines after an earlier treatment. There are several studies ongoing asking the question about this concept of an EGFR rechallenge. And this is based on our increasing understanding of the biology of resistance. Meaning that when patients are treated with an EGFR inhibitor, resistance clones can develop in the tumor, and these clones can then result in resistance.

Intriguingly, what we see is that with time after removal of the anti-EGFR therapy, those clones start to dissipate. And this is fascinating biology and really suggests that these clones are not fit in the absence of an EGFR selective pressure, and then they regress with alternate therapy in time. Others have modeled this and estimate that they regress with a half-life of about four months, which means that it does take time for them to regress, but with time, they can disappear; and we can assess that with ctDNA [circulating tumor DNA]. So there are interesting approaches of trying to rechallenge patients in later lines to try to restore sensitivity of anti-EGFR therapy.

I would discourage the continuation of anti-EGFR therapy in the second line if they received it in the first line, for example. And we really think that the more time between the exposures of anti-EGFR therapy, the better. While this can be guided by ctDNA, in many practical situations we really just use as much time as possible until we get to the point where the patient needs the treatment and then we return to the EGFR therapy. What we see is that patients can derive benefit. Usually it is not as high or as long a duration of benefit as their first exposure, but clearly the sense is that this can be beneficial to a subset of patients.

Transcript Edited for Clarity