Metastatic Colorectal Cancer: Advances in Non-Chemotherapy Treatment Options - Episode 5

Regorafenib Sequencing and the Future of Metastatic Colorectal Cancer Management

John Marshall, MD, speaks on regorafenib sequencing and relays his thoughts on the future of treatment for metastatic colorectal cancer.

John Marshall, MD: Possibly the biggest question you have is when to use what treatment. You have this menu. We’re telling you that you can use them in different orders and the like. When would you use regorafenib [REGO]? First, it has a different mechanism of action. It is suitable for patients who have seen a lot of chemotherapy where stable disease is an appropriate outcome, when you’re seeing a lot of fluoropyrimidine. That’s 1 type of patient who is an obvious choice for regorafenib, but there’s a fascinating study looking at using regorafenib before the EGFR [epidermal growth factor receptor] therapy. EGFR therapies are 1 of the places you will get a response. There’s a tendency to want to use that earlier, but what if you have a patient for whom you don’t necessarily need the response right now? They randomized patients between REGO first and cetuximab first. It was fascinating, and it showed that giving the REGO first caused patients to perform a little better regarding their overall outcome. This needs to be repeated to demonstrate that was a real phenomenon. In many ways, it gave us permission to flip the sequence on these.

Now as we know, cetuximab and panitumumab have their own challenges with skin reaction and the like, but the response generally overwhelms our thinking about that, and we say, “We’ll figure out the rash because we’re more likely to get a response.” As fewer and fewer people are candidates for cetuximab/panitumumab, because of our better understanding and profiling, we’re going to regorafenib earlier and earlier.

The other major competing decision is with TAS-102, or Lonsurf [trifluridine/tipiracil]. This is also an interesting drug. If you look at the phase 3 refractory studies, the results look almost identical. We have to remember that TAS-102 is a very different drug. It’s an oral chemotherapy. It’s a new kind of fluoropyrimidine, so it has a different adverse effect [AE] profile, 1 that has much more myelosuppression. The biggest AE we get into here is myelosuppression. It has a bit of an awkward dosing schedule, but there are some ways around that. There is also some newer evidence that if you give it with bevacizumab, for example—there was an interesting trial of TAS-102 and bevacizumab, comparing it with FOLFIRI [5-fluorouracil, leucovorin, and irinotecan] plus bevacizumab. It didn’t win, but at least it showed some benefit to some patients in that space. I think of TAS-102 more like another chemotherapy, but there’s still no responses by itself, so it‘s more of a maintenance chemotherapy where myelosuppression is the major AE, and there’s some benefit if you add [bevacizumab] to that.

Again, when do I use what in which patients? I like that switch of the mechanism of action. That’s 1 of my main reasons for using REGO first. I like that I have better control over the dosing, but I like giving patients a bone marrow break, so I know when I’m coming back with TAS-102 later, I’ll have a bit of a bone marrow break. There have been some studies with TAS-102 given after REGO where the reverse is not true, but we’re all evolving, so that’s an important study, but I don’t think it makes or breaks why you would use 1 or the other. The important thing is to make sure you get both on the chess board, and that both get a chance at a move to see if there will be benefit for your patients.

We think a lot about the reintroduction of chemotherapy. Let’s go back 2 years earlier, we started the patient with maybe 3 drugs, 2 drugs—I don’t know—and we backed them off to maintenance. We might still have OX [oxaliplatin] and IRI [irinotecan] on the table, then we’re going to come back to it later. I tend to wait and use that as a fourth-line approach because I might get a response, but I’m not going to get a big one. We must be honest about that. The longer the gap between, the better. I tend to not exhaust all my chemotherapy options, then go to REGO. I use REGO as an interval, as a break from chemotherapy, then I know that I still have those reintroductions on the table.

We’re not going to rest here, though. These 2 drugs have a role to play. Regorafenib is a useful drug in colorectal cancer, but we shouldn’t kid ourselves—we need more, and we need better therapies. There are some exciting things going on in the area of combination therapy. What has my highest level of attention right now is the combination of regorafenib and an IO [immune-oncology] therapy. There have been some publications about this, some phase 2 data, and some phase 1 data. There is now some expansion and replication of this data.

One of the common themes that is emerging so far is that in patients, primarily with lung metastases— don’t ask me why—we are seeing more benefit. The role that this carpet bombing TKI [tyrosine kinase inhibitor] might play in combination with other therapies is exciting. We are seeing more and more of that going on in our world today, so it’s about keeping a nose out for those things. Profile your patient, do broad molecular profiling, keep track of the profile in your HPR [health protection report]. This includes HER2 [human epidermal growth factor receptor 2], MSI [microsatellite instability], BRAF, all-RAS, etc, but also NTRK [neurotrophic tyrosine receptor kinase] and other rare mutations. You must know about those. You now need to know about tumor mutational burden, for example. You must know all those things. Use your chess pieces wisely. It’s about that time after that initial induction of therapy in the patient who is noncurable. It’s not how much chemotherapy you can give, but how little chemotherapy you can give, and you must manage that patient’s quality of life and progression of disease.

Yes, you can use NCCN [National Comprehensive Cancer Network] Guidelines, but remember that‘s a recipe that we expect you to fiddle with. I bet there’s nothing you make at home that you follow, maybe a cake, but beyond that, you would follow the recipe line by line. You throw an extra something here, take a little out there. The same holds true for patients with metastatic colorectal cancer. Through creative thinking, wise understanding of the drugs, and the strategy, you will see that you will get better survival for your patients, maintained quality of life, and better satisfaction on both sides. I hope this discussion has helped the audience understand the lines of therapy for metastatic colorectal cancer with an emphasis on maintenance and regorafenib.

This transcript has been edited for clarity.