Key Takeaways in the Treatment of Advanced Colorectal Cancer - Episode 5

Key Takeaway 5: Dosing of Multiple Kinase Inhibitors


Tanios S. Bekaii-Saab, MD: When we start thinking about patients beyond second line, so third or fourth line, we have 2 options right now, 2 oral options that are available to use, and they’re different options. Regorafenib is a multitargeted tyrosine kinase inhibitor [TKI]. It hits VEGF but also hits FGFR and CSF1R and all these other things. On the other hand, TAS-102 belongs to this superfamily of fluoropyrimidines. It’s not technically capecitabine or 5-FU [5-fluorouracil] because it’s equipped essentially to fight some of the elements that drive resistance with 5-FU [5-fluorouracil] and capecitabine. So it has activity beyond 5-FU [5-fluorouracil], but it’s a cytotoxic agent, so there are different mechanisms.

They’ve never been compared head-to-head, and so it’s very difficult to say if one is preferred over the other because of the lack of a randomized approach to compare the 2. Historically, they seem to perform equally well, except they seem to have different levels of toxicities. For example, regorafenib has more hand-and-foot syndrome reaction, which essentially can be detected very early, within 15 to 20 days. On the other hand, TAS-102 [trifluridine, tipiracil hydrochloride] ends up with more hematologic toxicities. The GI [gastrointestinal] toxicities are somewhat similar between the 2, maybe a little worse with TAS-102 [trifluridine, tipiracil hydrochloride] when they looked at a large Japanese cohort. It was in 1 institution cohort with the 2 agents. And I think it’s about the same. Fatigue is about the same. So most toxicities are about the same.

With regorafenib, the standard dosage that’s approved is 160 mg orally on a daily basis, 21 days to 28 days. We recently published results from the ReDOS trial, the Regorafenib Dose Optimization Study, that actually looked at a different way to give regorafenib in which you start with 80 mg, go to 120 mg, go to 160 mg as tolerated. It’s on a weekly basis, and then take a week off versus the 160 mg, 21 of 28. Interestingly, that study essentially reached its primary endpoint, and our primary endpoint was essentially a composite of both efficacy and toxicity.

In other terms, what this study essentially showed us is that if we look at the percentage of patients who are able to start cycle 3, you have to respond to the agent, and you have to be able to tolerate the agent to be able to move to cycle 3. We had at least 17% to 18% more patients get to cycle 3 with a dose-escalation strategy versus the standard-dose strategy. The toxicities were reduced. The quality of life of the patients was preserved with the regorafenib 80 mg to 120 mg to 160 mg. Intriguingly, the survival of patients actually looked better, although statistically it was not significant, but clinically I think it was meaningful. It was 10 months, the dosage-optimization schedule, meaning 80 mg to 120 mg to 160 mg versus close to 6 months on the 160 mg, which is what you expect with 160 mg.

For all these purposes, the ReDOS schedule has become our standard practice with 80 mg to 120 mg to 160 mg, and that also, because historically it seems to do better than the rego [regorafenib] 160 and historically also seems to do better than TAS-102 [trifluridine, tipiracil hydrochloride]. In fact, we published recently a network analysis that did suggest that there are these advantages with the 80 mg, 120 mg, 160 mg versus 160 mg and the TAS-102 [trifluridine, tipiracil hydrochloride]. In our practice, every patient that’s eligible starts with regorafenib first and then TAS-102 [trifluridine, tipiracil hydrochloride] following regorafenib failure.

There are exceptions to this. A patient may have had issues with hand-and-foot syndrome with capecitabine—a different reaction but still noxious enough. Or a patient is borderline performance status—those patients actually will start with TAS-102 [trifluridine, tipiracil hydrochloride]. For those patients also with some liver dysfunction, a bit reluctant to go with regorafenib, those patients would go on TAS-102 [trifluridine, tipiracil hydrochloride]. But the majority of the patients will start with regorafenib followed by TAS-102 [trifluridine, tipiracil hydrochloride].

Transcript Edited for Clarity