TAS-102 in Third or Fourth Line for mCRC

John Marshall, MD: Let’s spend a few minutes on an equally important drug, TAS-102 [trifluridine, tipiracil]. I can remember we used to call it CPT-11 before we got over that. But TAS-102 is what we call it now, trifluridine tipiracil, Lonsurf, the trade name. This is a different drug, right? It’s fluoropyrimidine of sorts, myelosuppression, the main adverse effect. But also very similar, if not identical, curves in terms of PFS, [progression-free survival] in terms of OS [overall survival]. Again, similar populations, similar trial design. And I think of the 2 drugs as not interchangeable. You decide you’re going to use one versus the other based on the biology that’s already been declared for the patient, what adverse effects have they endured.

But I also see there are more and more data with TAS [trifluridine, tipiracil] being used in combination with BEV [bevacizumab], and in earlier lines of therapy and chemotherapy. I see it as one of those interchangeable chemotherapy chess pieces that might end up replacing capecitabine after you’ve progressed on CAPE [capecitabine]. But for the same things we talked about with REGO [regorafenib], we also have this other compound that needs managing, the toxicity, and different sets of toxicities, but one that is equally important to try not to leave on the table when you’re playing chess against chronic disease. What do you think?

Axel Grothey, MD: Yes, I completely agree. In the end patients benefit from having all active agents as part of their treatment. And TAS [trifluridine, tipiracil] is an active agent. We have phase 3 data, 2 sets of phase 3 data. A kind of Western world plus Japan study, the RECOURSE study, and the TERRA study, similar to CONCUR with regorafenib in the Asian patient population. This drug is active, no question.

You mentioned fluoropyrimidine. It’s even active in patients who have been pretreated with 5-FU [fluorouracil]. It has a little bit of a different mechanism of action. It doesn’t cause hand-foot syndrome, different than capecitabine; it’s an oral agent.

It has an interesting and strange dosing schedule if you think about it, twice a day for the first 5 days, and then from day 8 to 12. It’s repeated every 4 weeks, but a lot of patients won’t be able to continue after 4 weeks because they have severe neutropenia, in particular with all these pretreatments we have. It’s interesting. It is more a standard chemotherapy that we have. It’s not the fancy biologic agent, or an I/O [immunotherapy] agent. But as you mentioned, I think it deserves attention because it combines well with bevacizumab, like very fluoropyrimidine combines well with bevacizumab.

We have randomized data in a later-line setting from a Danish group that showed BEV [bevacizumab] plus TAS [trifluridine, tipiracil], it leads TAS [trifluridine, tipiracil] alone in progression-free and overall survival. That’s what I try to use, and normally can use, because we have published randomized data. I combine TAS [trifluridine, tipiracil] with bevacizumab unless there is a contraindication.

Even the first-line data, as you mentioned, TAS [trifluridine, tipiracil] and BEV [bevacizumab] versus CAPE and BEV [capecitabine, bevacizumab], with a trend in outcomes improvement numerically but not significant in progression-free survival. But again, I think it’s a drug that should be used, should be part of our portfolio of agents. And I believe that the pool of patients who are candidates for TAS, [trifluridine, tipiracil] because it has fewer subjective adverse effects than regorafenib, is probably larger. Then we would not treat patients with PS2 [performance status of 2] with regorafenib.

There are some patients when we talk about treatment options with PS2 who I would treat with TAS-102 [trifluridine, tipiracil]. This in some ways also influences my sequence of events because you can have a big discussion. Regorafenib first or TAS [trifluridine, tipiracil] first. They have similar activity. I normally in most patients use regorafenib first now that we know how to dose it. We give patients a break from cytotoxic therapy, bone marrow gets a break. And we have data for TAS [trifluridine, tipiracil] after [regorafenib]. We don’t have the data for regorafenib after TAS [trifluridine, tipiracil]. I believe even if the performance status of patients might deteriorate on regorafenib, they might still be candidates for TAS [trifluridine, tipiracil], but not vice-versa.

The likelihood is higher that patients get both agents if you do regorafenib first and then TAS [trifluridine, tipiracil]. That’s what I use. I don’t what you’re doing in your clinical practice.

John Marshall, MD: You never heard me say this and the 200 people who are online now, I’ll deny it. Just give TAS [trifluridine, tipiracil] every other week, it solves the problem. It really does. It lines up very nicely with BEV [bevacizumab] as well.

Axel Grothey, MD: It’s really complicated.

Transcript Edited for Clarity