mCRC: Second-Line Treatment Decisions

Axel Grothey, MD:When we look at the second-line treatment choices that we have available, our decisions, of course, depend on what we did in the first-line setting. We could switch chemotherapies out, from oxaliplatin to irinotecan-based therapies. We could continue bevacizumab or VEGF inhibitors beyond progression, or switch to the EGFR antibodies.

So second-line choices clearly depend on first-line treatments, and of course, on biologic parameters, molecular parameters, like for instance,BRAFmutation testing. ForBRAFV600E-mutated tumors, which are a very specific group—8% to 10% of patients—we now have second-line data with a completely biologically oriented treatment approach with a combination of an EGFR antibody inhibitor and a BRAF inhibitor, like encorafenib. Those patients actually benefit from a biologic approach more than from second-line chemotherapy. It really depends on first-line treatment and molecular parameters, regarding what we like to do in the second-line setting. And of course, the idea of immunotherapy comes into play for the patient with an MSI [microsatellite instability]-high tumor.

When we talk about moving from 1 line or 1 treatment to another, the factor that comes into play is clearly tumor progression, or relevant tumor progression. Sometimes I observe smoldering progression on maintenance therapy, which is not clinically relevant, so I might keep patients on maintenance therapy. But if you see clinically relevant progression, which is not clearly fully defined as to what that is—sometimes we don’t necessarily use RECIST [Response Evaluation Criteria in Solid Tumors] criteria in clinical practice to talk about clinically relevant progression—then we switch treatment. So, clinically relevant progression plus if patients don’t tolerate treatment.

There are patients who cannot tolerate oxaliplatin-based therapy. Hypersensitivities, for example, to oxaliplatin could trigger a change in therapy to irinotecan-based therapy, etcetera. It really depends on toxicity and progression of disease. These are triggers for switching to a different regimen.

When we talk about sequencing of agents and look at EGFR antibodies versus later-line therapies like regorafenib and TAS-102, there’s a recent very interesting study that we’re still struggling to understand, the REVERCE study from Japan, which looked at giving an EGFR antibody plus irinotecan first, before regorafenib, or regorafenib before the EGFR antibody option in aKRASwild-type tumor population.

The study was a sequential study, randomized comparison, and had a very surprising result. There was a 6-month benefit in overall survival for the earlier use of regorafenib—regorafenib before EGFR antibody therapy. We still don’t know exactly why that is. There’s a hypothesis that the earlier use of EGFR antibodies induces resistance mechanisms in cancer cells. This means we see the emergence ofRAS-mutated clones, and that’s actually something we can test with circulating tumor DNA nowadays. TheseRAS-mutated clones, which are selected under the pressure of an EGFR antibody, could drive more aggressive biology. When we use EGFR antibodies in later lines of therapy, this might actually not be as important because the duration of therapy at that point is shorter.

So we’re still struggling with the idea of how to best sequence these drugs. In my clinical practice, I have not yet embraced the study’s sequence. I use EGFR antibodies inRASwild-type,BRAFwild-type left-sided tumors before I use regorafenib.

Transcript edited for clarity.