Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Axel Grothey, MD: The goal of our treatment, as I mentioned, is to really make all agents available to all patients. And fortunately after a long period of no treatment options with overall survival benefit in the third-line setting, now we do have relevant options. I mean, before we used FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin] followed by FOLFIRI [folinic acid and irinotecan] with the addition of antibodies—bevacizumab and EGF receptor antibodies—but now we have new classes of agents and new agents that can really improve survival. And based on actual phase III data with regorafenib and TAS-102 [trifluridine], which is an oral fluoropyrimidine, actually fluorothymidine. Those oral agents have shown efficacy in a third- and even fourth-line setting for patients with unselected metastatic colorectal cancer.
Then the arm, the more selected options for a patient with the BRAF V600E–mutant tumors and the immunotherapy for a patient with MSI [microsatellite instability]–high cancers.
Tanios Bekaii-Saab, MD: You’ve gone through 2 lines of therapy, sometimes 3, but for most patients we go through 2 lines of therapy. If you’re on the right side, you go chemotherapy– bevacizumab, chemotherapy– bevacizumab, and then you have the decision about whether I should go to regorafenib or TAS-102. In the RAS wild type, one could again think, “Well, should I, instead of an EGFR first, on the right side? Should I consider an EGFR inhibitor first before I proceed with regorafenib or TAS-102?” I think the answer is a little more complex. We haven’t seen a lot of signals with EGFR inhibitors on the right side, and I think you introduce perhaps regorafenib before cetuximab or panitumumab.
Then we have this data from Japan from the REVERCE trial that looked at regorafenib first followed by cetuximab and cetuximab first followed by regorafenib. And the study, although underpowered, did reach its primary endpoint of showing a survival benefit if you move regorafenib ahead of cetuximab. On the right side, I feel very comfortable having regorafenib in the third line, and then I will consider actually, after regorafenib, TAS-102 and then perhaps cetuximab.
On the left side, and those patients with RAS mutations or those patients with BRAF mutations, HER2 amplifications. For the HER2 amplifications let’s table that discussion, because those patients probably should go on a clinical trial with HER2-targeted therapies, a TKI plus trastuzumab. This is a separate subgroup that probably is a little complicated. But for the other patients who may not be eligible for EGFR inhibitors, then you go bev-chemo [bevacizumab-chemotherapy], bev-chemo, and then your third line is either regorafenib or TAS-102. There’s no discussion about an EGFR inhibitor there. How you choose between regorafenib or TAS-102 really depends on looking at the globality of the data.
We recently presented some data, and this is now accepted into publication by the oncologist who looked at all the randomized trials with TAS-102 and with regorafenib, including the ReDOS trial, which looked at the dose escalation strategy of 80 to 120 to 160 mg on a weekly basis, which we’ve shown is superior strategy to 160 mg. When we look at the cumulative knowledge with regorafenib and TAS-102, what becomes clear from this analysis is that regorafenib with a dose escalation strategy is superior to regorafenib 160 mg, but it also may be superior to TAS-102 in terms of outcomes. Not reaching the level of statistical significance but enough to say that this essentially is meaningful, at least clinically meaningful.
The other pieces of data come from having a large amount of data coming from subset analysis from multiple studies. And when we look essentially at the studies that were done primarily in Asia, like CONCUR and the TARA, what becomes apparent to us is that from the cumulative knowledge is that regorafenib seems to have a better effect if we expose patients to it earlier as indicated rather than later in the refractory setting. And that’s true for the CONCUR trial. The TARA trial tells us that TAS-102 keeps its activity, regardless of pre-exposure.
We have REVERCE-2 that will be ongoing in the United States. We do need to confirm here whether moving regorafenib ahead of cetuximab makes sense. But REVERCE also challenges us at the point of understanding that regorafenib seems to have a much better effect when you move it up rather than let patients go through all the lines of therapy and use regorafenib as a Hail Mary effect. It doesn’t have much activity there. It seems to have more activity when you move it up. So my preference is essentially in the sequencing of therapies, to go with the regorafenib first, then TAS-102. On the right side, regorafenib, then TAS-102, then cetuximab or panitumumab.
The bigger question is, of course, whether there are there patients for whom you would move TAS-102 ahead of regorafenib. And the answer is yes, if you have a patient who has borderline liver function and who has significant liver metastases, meaning that the liver functions look pretty upset. I’d probably favor TAS-102, as long as they’re within reason. If they’re very upset, then both drugs should not be given. I would also consider it for the patient who may have experienced significant hand-and-foot syndrome reactions from other agents, although this is again not the same reaction. It’s similar in some aspects, but those are the patients who probably would not want to go through another agent that can affect them that way. Those patients may go to TAS-102.
On the other hand, if your preference is to start with TAS-102 first—I don’t do that, but if your preference is to do that—then those patients who may have experienced significant bone marrow toxicity from other agents should probably not go on TAS-102 or should go with extreme caution because TAS-102 can induce significant hematologic toxicities.