Therapeutic Strategies in Metastatic Colorectal Cancer - Episode 12

The Role of TAS-102 in Metastatic Colorectal Cancer

Transcript:John L. Marshall, MD: Just as we’re figuring this out, here comes another drug: the TAS-102 drug. Richard, walk us through the clinical trial and the impact of this drug.

Richard Kim, MD: Sure. So, the new drug is TAS-102, which is an oral 5-FU that’s basically composed of tipiracil and trifluridine. This is a little bit different than your capecitabine. Your capecitabine is a pro-drug 5-FU that inhibits TS. This is an active component, this is the trifluridine, which is actually getting incorporated in the DNA synthesis. So, it’s a little different, mechanistically, compared to capecitabine. This drug was studied in a phase III study, called the RECOURSE study—very similar to the CORRECT study—where patients must have failed standard chemotherapy. The difference is that in this subset population, 20% of the patients got regorafenib, because the drug got approved, some patients got exposed to it. And the primary end point was overall survival, and they looked at the PFS and response rate as well. And the outcomes were that patients who were getting TAS-102 had about 2 months overall survival. The progression-free survival was almost identical to the CORRECT study. And, unfortunately, even though this is a cytotoxic chemotherapy, the response rate was about 2% to 3%; very low response rate. So, based on those findings, the TAS-102 is now commercially available for us to use in patients who failed the standard chemotherapy.

John L. Marshall, MD: And I think a lot of these patients, too, had just come off of 5-FU, so the question is, is this just a re-challenging of a fluoropyrimidine versus a continued approach? What’s this telling us about colon cancer in the refractory setting? Keeping a little something going. We’ve got a multi-targeted tyrosine kinase inhibitor. We’ve got a little novel chemotherapy. What’s it telling us about the biology of the disease?

Charles S. Fuchs, MD, MPH: Well, I think these two studies for TAS-102 and regorafenib tell us two important things. One is, keeping VEGF inhibition—in this case, the regorafenib—throughout the course of treatment is a good thing in reducing progression of disease. And, that with regard to TAS-102, keeping a fluoropyrimidine around is a good thing. There were studies, as you may recall, with capecitabine in the refractory setting that said maybe there was some disease stabilization.

John L. Marshall, MD: And everybody said no response, so it doesn’t work, but we now appreciate an improvement in progression.

Charles S. Fuchs, MD, MPH: Yes, and arguably, maybe the logical answer is give TAS-102 and regorafenib together, because both VEGF inhibition and a fluoropyrimidine, continued through the natural history of treatment, is a good thing.

John L. Marshall, MD: Yes. So, we’re starting to see some of those combinations. Toxicity? You’ve been giving this drug out some?

Johanna Bendell, MD: Yes, definitely. And I think there’s a definite toxicity difference between the two agents. In our hands with the TAS-102, we’ve seen more of a neutropenia effect, a blood count effect than anything else.

John L. Marshall, MD: And a profound one, too. They come back a month later and their ANCs are 300, and for GI oncologists, that freaks us out. We don’t do neutropenia, right? Does it read the same way? Like oh gosh, what should I do?

Johanna Bendell, MD: Definitely. But they don’t get that fatigued. They don’t get the hand-foot syndrome; so, very different in terms of choosing which agent you’re going to use based on what the toxicity profile is.

John L. Marshall, MD: We’ve seen a certain number of patients having that low-level nausea; most are not. For most, it’s very well tolerated, but there is that subset. We say, oh, it’s an easy drug, but there is that group that’s having that—everybody has seen that, too—10% to 20% subset.

Tanios Bekaii-Saab, MD: Absolutely.

Charles S. Fuchs, MD, MPH: It’s an issue where you have to delay the next cycle. I’m sure we’re all seeing it. They come in for the next prescription, and they’re neutropenic. They feel fine, but their counts are low.

John L. Marshall, MD: Funny regimen, too. So, 5 days on, 2 days off, 5 days on, 2 weeks off. It’s a little funky that way. I think, same as we’ve discussed with regorafenib, we’re going to be fiddling with the dosing schedule of this drug as well. Both are going into other studies in combination, in maintenance, and in other combinations. Anything there to publish, or we’re just starting that process?

Tanios Bekaii-Saab, MD: Starting the process.

Transcript Edited for Clarity