Optimal Sequencing in Later Lines of Therapy for mCRC - Episode 5

mCRC: Third-Line Treatment Decisions

March 20, 2020

Axel Grothey, MD:The data that we’ve seen in clinical observation studies regarding how many patients really make it to third-line and fourth-line therapy vary. This might be where the differences between specialized centers versus nonspecialized centers come into play.

Specialized centers that include experts in colorectal cancer management probably have a higher likelihood of moving patients through lines of therapy in this continuum of care. In my clinical practice, I try to make sure that more than 50% of patients will make it to a third-line treatment setting, for which we can make a decision to treat with regorafenib, TAS-102, a clinical trial, etcetera.

Now, what we see in the data a national level, it’s much lower. We see that about 20% to 30% of patients might make it to a third-line treatment setting, and then have the choices available to them that we talked about.

The decision in a third-line therapy setting regarding which agent to use—EGFR antibody, if patients have not received the EGFR antibody yet, or regorafenib, or TAS-102—really depends on a lot of different factors.

The benefit of regorafenib by itself is that it’s no chemotherapy. By the time patients come to the point of third-line treatment, they may have had a lot of exposure to chemotherapy, bone marrow suppression, etcetera. So having a noncytotoxic agent wedged in can actually give a patient’s bone marrow the chance to recover. This might be particularly useful for patients who had infectious complications, issues with neutropenia, on prior lines of therapy, which could be related to some pharmacogenomic difference they have. Regorafenib could be a nice interval.

There’s also the idea, and we’ve actually tried to explore this, whether regorafenib—this multikinase inhibitor that really targets a lot of different kinases involved in tumor biology, tumor progression, tumor host interaction, immunology, etcetera—might actually re-sensitize tumors to chemotherapy. So this is really a biologic switch that might turn tumors into chemosensitive tumors. Or, it’s just what I mentioned before, giving a patient a break from chemotherapy, which we know can lead to the emergence of chemosensitive clones again. We don’t know that. But I do believe—I’ve seen this in patients who I’ve treated—that patients, after regorafenib, responded to chemotherapies they have progressed on before. So there is actually this idea of exposing patients to chemotherapy again after regorafenib. That is a valid option for patients.

Now, in clinical practice, if patients have not seen an EGFR antibody and they come to third-line treatment, if they have a left-sidedRAS/BRAFwild-type tumor, I would still use an EGFR antibody before I embark on TAS-102 or regorafenib.

TAS-102, again, is a reliable fallback option for patients with a poor performance status who might not be good candidates for regorafenib, if you talk about the optimal sequence.

Transcript edited for clarity.