mCRC: Sequencing With Regorafenib or TAS-102

Axel Grothey, MD:Coming back to the idea of continuum of care, later-line treatment approaches add to survival. We’ve known this for quite some time. Until recently, we didn’t have a lot of interesting third-line or fourth-line treatment options. Now we actually have 2 distinct agents—regorafenib, a multikinase inhibitor, and TAS-102, which is a fluoropyrimidine, fluorothymidine chemotherapy. Those agents are now competing for the third-line space. The question is, how do we sequence these treatments? Who are these patients who should receive 1 drug or the other?

They have very distinct differences in not necessarily efficacy, but toxicity. TAS-102 is a chemotherapy agent, conventional chemotherapy. It’s main adverse effect is neutropenia. We actually know that patients who develop neutropenia have a better outcome on TAS-102 than patients who don’t develop neutropenia. This neutropenia is relatively asymptomatic. Patients normally do not have febrile neutropenia, so a lower rate of infection, and some patients might have diarrhea or fatigue. But normally TAS-102 is quite well tolerated.

The pool of patients I consider for TAS-102 is larger than for regorafenib, because regorafenib has subjective toxicities—hand-foot skin reaction, rash, fatigue, loss of appetite.

Now, we want to make sure that patients receive all active agents. That’s one of the key principles of dealing with metastatic colorectal cancer patients. So how do we ensure this best? And this is where the evaluation of toxicity comes into play. I do believe that a patient who is a candidate for regorafenib in the third-line setting should receive regorafenib before TAS-102. If we choose TAS-102 first, when patients’ performance status [PS] deteriorates, these patients might not be good candidates for regorafenib anymore.

With the goal in mind to really expose patients to all active agents, it is more prudent to use regorafenib first followed by TAS-102 in patients who are considered candidates for regorafenib. Again, the pool of patients considered for third-line treatment is probably larger for TAS-102 than for regorafenib. I would not treat a patient with a PS2 with regorafenib, but I would treat a patient with PS2 with TAS-102 up front.

This might actually change now that we have interesting data combining regorafenib with immunotherapy and TAS-102 with bevacizumab. These are new developments, new combination therapies. We will need to see what place they’ll have in the third-line treatment setting.

Transcript edited for clarity.