Sequencing in mCRC: Later-Line Therapies

Axel Grothey, MD: When we initially looked at patients who actually got off regorafenib and then were in good shape and wanted to be treated, even outside clinical trials, we observed that when we re-challenge with agents that had been used before regorafenib, even patients who progressed on these regimens before regorafenib, might have a response stable disease after regorafenib. I remember 2 patients who triggered my interest in that, who had progressed on the fluoropyrimidine plus bevacizumab before regorafenib and responded really beautifully after regorafenib and quite long lasting. We actually discussed this and looked at preclinical data and clinical data. We did a joint analysis between the Mayo Clinic, [The University of Texas] MD Anderson [Caner Center], and the USC [Norris Comprehensive Cancer Center] and did actually collect patients where there was this idea of a clinically recent sensitization effect. We don’t know whether this is just based on the fact that regorafenib as a nonchemotherapy drug gives patients time off cytotoxic therapy, and just through this time effect allows clones to reemerge that eventually are sensitive to chemotherapy. It could just be a time effect. The other question would be, Is it a biological effect? Because regorafenib is a multikinase inhibitor, it is involved in a lot of biological phenomena. That really characterized cancer cells, including chemosensitivity, that adding regorafenib to chemotherapy, 5-FU [5-fluororacil]–based, irinotecan-based, even EGFR antibodies, suggests there is some additive-synergistic effect. But I do believe we need to really work on these animal models more, and it’s not easy to design the right animal models because regorafenib’s activity could be related to various different things, including angiogenesis inhibition and microenvironment modulation, pathway inhibition within tumor cells, and also modulation of the immune system. All these factors are not very easy to test in an animal model, and animal models might not be fully predictive of what’s happening in humans.

Fortunato Ciardiello, MD, PhD: A very important question is when we decide to use either regorafenib or TAS-102 [trifluridine, tipiracil hydrochloride], which is the best to use before and which is the best to use after? I guess we have no evidence in the literature so far that is suggesting that 1 sequence is superior to the other. In other words, in my opinion, my preference is more based on which are the treatment goals, which are the adverse effects that I would like to avoid for the patient rather than what to expect in terms of activity or efficacy. Therefore, I treat with regorafenib followed by TAS-102 or vice versa based more on what is the natural history of the disease, how the patient was treated, and which lines of treatment were given before. I also treat in terms also of adverse effects in treatment, rather than thinking of giving regorafenib before TAS-102 is better or giving TAS-102 before regorafenib is better. I don’t think we have these data, and I think we will never have these data in the general population of patients.

Heinz-Josef Lenz, MD, FACP: That’s an ongoing question, what is the best 1 in third-line? When you look at the efficacy profiles, they’re very similar. In the future that may be answered with new data coming out with TAS-102 and bevacizumab showing nice overall survival data as well as regorafenib with immune checkpoint inhibitors. We may learn much more in the future about what combinations we should use. In general, what we learned with regorafenib is that it is important to use it in earlier-lines of treatment as well as in younger, fit patients compared with TAS-102. That’s what we use as a direction to make the most effective treatment decision and most convenient treatment decision for the patient.

Fortunato Ciardiello, MD, PhD: A possibility then is combining TAS-102, which is a fluoropyrimidine, with regorafenib, which is an antiangiogenic agent. The question is, is it worth it to do the 2 drugs together, or is it better to do the 2 drugs in sequence? It’s very complex to give an answer. First, we need the randomized phase 3 data really to show if combining the 2 of them is better than giving each alone followed by the other. Because, for sure, we are putting together 2 different types of toxicities with 2 drugs that most likely will be both cytostatic rather than cytotoxic. We have to see if combining the antiangiogenic properties of regorafenib and antimetabolite properties of TAS-102 is worth it in terms of enhanced activity.

Axel Grothey, MD: Regorafenib has been used mainly as a single-agent treatment, and it’s being recognized as one of the standards of care. Now, regorafenib could potentially land itself for combination therapy with an agent that does not have overlapping toxicity, like TAS-102. TAS-102 has a very different toxicity profile from regorafenib; they do not overlap. There is a single-arm, phase 1b study for early experiences with the combination of regorafenib and TAS-102, and the data are very preliminary so far. I do believe this is an interesting combination that could move forward, but we definitely need to have randomized data to show that. Other combinations are regorafenib in combination with immune checkpoint inhibitors, like nivolumab. I believe regorafenib is 1 of those drugs that can augment immune response through various mechanisms, such as macrophage population shift, that needs to be explored further. We have preliminary data that are very interesting.

Transcript Edited for Clarity