Case 3: Third-Line Therapy for Metastatic CRC

Shubham Pant, MD:Greg, Richard brought upTRKfusions, and there’s a new kid on the block. Are you testing for all of theNTRKfusions? We’ve seen very high response rates in theNew England Journal of Medicinepaper across all of theseNTRKfusions.

Gregory Riedlinger, MD, PhD:We’re generally not doing that up front. Up front, we’re just doing theKRAS,NRAS,BRAF^V600E. And then, if the patient becomes refractory, we’re sending to Foundation Medicine. What has generally been reported in colon cancer is NTRK1 and NTRK3. And then, obviously, as we kind of talked about withALK,ROS, andRET, it’s smaller percentages. One take-home message for places that aren’t routinely sending all of these up front is, it seems like these rearrangements tend to be found more often in older patients with microsatellite instability—high tumors. They also tend to beKRAS- andBRAF-negative. That might be 1 subgroup to send or to think more about.

Shubham Pant, MD:That’s an excellent point. Richard, I’ll come back to you. For our patient, let’s say there are no targetable mutations. You do NGS [next-generation sequencing] testing. You may use FOLFOX [folinic acid, fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, fluorouracil, and irinotecan], bevacizumab, or cetuximab. Then you come to the third-line setting. What do you normally choose as your third-line agent? How do you pick among the agents?

Richard Kim, MD:In the third-line setting, when you fail standard chemotherapy, there are 2 oral oncolytics available. One is TAS-102, and the other is regorafenib. There’s no head-to-head comparison so we cannot say one is better than the other. They both showed an overall survival benefit compared to placebo. The mechanism is different. Regorafenib is a TKI [tyrosine kinase inhibitor] that blocks multiple pathways. TAS-102 is a combination of trifluridine [Viroptic] and tipiracil. The trifluridine actually gets incorporated into DNA, preventing DNA synthesis. Tipiracil is a thymidine phosphorylase inhibitor. So the mechanism is totally different.

The only difference I see is that the toxicity profile is different. As Mike mentioned, with TAS-102, the main toxicity is hematologic. There may be a little fatigue, so the counts will drop. On the other hand, with regorafenib [Stivarga], the most common toxicities are probably hand—foot skin reaction, fatigue, and rash. Diarrhea may also be an adverse event. How the patient looks phenotypically in the third-line setting determines what I would choose. For example, if the patient had a lot of problems with hand–foot skin reaction with 5-FU [fluorouracil], I’d probably choose TAS-102. However, if the patient had neutropenic fever or grade 4 neutropenia, I would probably stay away from TAS-102 and go with regorafenib. And with the data from the ReDOS study, where you could actually start at a lower dose of 80 mg and escalate the dose up to 160 mg without compromising efficacy, if I do start on regorafenib, that’s what I would do in this setting.

Shubham Pant, MD:This is probably what people were doing in the clinical setting before the ReDOS data came out. And so, has that changed your practice or was that something that you were already doing in your practice?

Michael Morse, MD:I think it’s important that we have validation of what we do in clinical practice, because that has been the tendency in medical oncology: to evaluate the patient and then decide what you think they can tolerate. But, of course, it’s entirely possible that we would be underdosing people. So not a lot of toxicity, but not a lot of benefit. I think this just gives us comfort for what we were already doing.

Transcript edited for clarity.