John L. Marshall, MD: Let’s consider a patient who is microsatellite stable; is unresectable; has had oxaliplatin-based therapy; has had irinotecan-based therapy; has had the appropriate biologics, depending on their characterization at that point; still has an excellent performance status, 0-1; and now, 2 years later, or 18 months later since you first met, they’re unresectable for metastatic disease. Can you describe the distinction and what you think about rechallenge versus reintroduction?

The way I like to think of it, are the chess pieces still on the board, and can you move them again? Or are they not? Paul, why don’t you define for me what you think of a drug that’s still on the board that you’ve played once?

Paul R. Helft, MD: In general, for patients who’ve had adequate exposure to irinotecan, a fluoropyrimidine, oxaliplatin, and the antibodies, for which I consider refractory and would almost never find a good reason to go back to using...

John L. Marshall, MD: Let’s say they only had 4 months of oxaliplatin, and you stopped it after a nice partial response.

Paul R. Helft, MD: I would have already reintroduced it in the first-line setting, before I would have ever switched to irinotecan.

John L. Marshall, MD: It’s already been played?

Paul R. Helft, MD: Exactly.

Fortunato Ciardiello, MD, PhD: I agree. We are really focusing on refractory patients—patients in which we think about everything we do as strategy in our first-line and second-line work—and then we failed. This is a patient who is a candidate either for experimental therapy or for TAS-102 or for regorafenib. Then the question will be, what are the 3 things I will do?

John L. Marshall, MD: I’m seeing a distinction here about: “Did you progress on it, or have you already replayed it?” And I’m seeing people using another VEGF when they’ve already progressed on a VEGF. Or you use a lot of EGFR, again, if they had frontline therapy, and then you did VEGF in the second-line setting.

Fortunato Ciardiello, MD, PhD: Yes, but in first-line therapy—left-side tumor, anti-EGFR—let’s consider that this patient responded. Then you did the second-line therapy, without chemotherapy, with bevacizumab, and they respond. And now he’s really in progression. I think that for first- and second-line therapy, we have done whatever we could have done for the patient. And actually, the patient has a metastatic disease that is more than 1-year enough. Because this magic number tells you that these types of patients are surviving with therapies, these patients are more likely to possibly have a benefit by either TAS-102 or regorafenib. That will be my first option.

John L. Marshall, MD: This is where I want to sort of challenge this discussion. Paul’s got this strategy of reintroducing right away. I tend to not. I hold it because I’m not sure of any survival benefit there. The EGFR, too, is emerging, but there is still no survival benefit. Whereas I’ve got 2 medicines, TAS-102 and regorafenib, that have survival benefit. Should there be a strategy of using those drugs before a rechallenge?

Dirk Arnold, MD, PhD: The immediate reintroduction, as you are suggesting, can be done later. We should not forget that this patient was not progressing on the oxaliplatin. This can be used later.

John L. Marshall, MD: Immediately challenge?

Paul R. Helft, MD: To push back on your evidence-based medicine comment earlier, we have some data—not randomized data, obviously—for reintroduction or early reintroduction. We have very little to say about oxaliplatin after fourth-line therapy.

Dirk Arnold, MD, PhD: They have data from immediate reintroduction and from later, with even better rates from later reintroduction.

Fortunato Ciardiello, MD, PhD: But in terms of toxicity, for example?

John L. Marshall, MD: These are experiences, too. They’re not really tight trials, but it legitimizes doing it. Everybody is saying that. What I’m sort of drilling down on is, when and how?

Tanios Bekaii-Saab, MD: So, your question is mostly about the timing?

John L. Marshall, MD: Yes.

Tanios Bekaii-Saab, MD: Do we do it when we think we should per OPTIMOX or per OPTIMIRI, or can we do it later? In OPTIMOX and OPTIMIRI, you can actually find evidence for that. For the later lines, it is possible. We all see these patients that have come in as referrals. They went through 4 months of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), and then went on maintenance therapy for 6 to 10 months. When they progressed, they went on FOLFIRI (folinic acid, fluorouracil, and irinotecan). So, the question when they come to your clinic after 2 lines of therapy is, should we take them back to FOLFOX? This is where I agree with John. I think that the significant evidence lacks. There may be some, but the evidence lacks.

Dirk Arnold, MD, PhD: But, it’s the same whether it is early or later.

Tanios Bekaii-Saab, MD: Hold on. No. You skipped a therapy. This is FOLFOX or FOLFIRI, and you still think oxaliplatin hasn’t been reintroduced. The significant evidence lacks. There is some evidence. And, clinically, we know that there are some patients, but I would actually move this to fifth-line therapy rather than to third-line therapy.

Dirk Arnold, MD, PhD: This is to be discussed.

Tanios Bekaii-Saab, MD: I wouldn’t say that it’s to be discussed.

John L. Marshall, MD: Yes, there’s no right single place to put it.

Tanios Bekaii-Saab, MD: It needs to be studied.

Fortunato Ciardiello, MD, PhD: Two lines. With TAS-102 and regorafenib—that, we can discuss for hours—what is better to do before? What are the differences in terms of toxicity?

John L. Marshall, MD: We’re not going to spend hours, but we’re going to discuss it.

Fortunato Ciardiello, MD, PhD: The concept is, when I finish all the potential in the first 2 lines of therapy, I have these 2 options, especially if the patient survived so long to first- and second-line, maybe the patients will respond to a sequential treatment with these 2 drugs. We already said that if a patient responds to regorafenib, there are higher chances to respond to TAS-102 and vice versa in this patient population.

John L. Marshall, MD: Probably biology that we’re finding here, too.

Tanios Bekaii-Saab, MD: Yes, absolutely. There are data. They’re retrospective from the Mayo Clinic, MD Anderson Cancer Center, and others, revealing that, essentially, when you expose patients to regorafenib—this is before TAS-102 was approved—and you rechallenge or reintroduce, that you still see some really decent response, and you don’t lose the benefit from the chemotherapy after you go through these later lines of therapy.

John L. Marshall, MD: I’m old enough to remember being so excited about any new medicine for colorectal cancer and, particularly, one with an overall survival advantage. Every time one of my patients does not get these 2 medicines, I feel a little bit like I’ve not done my job. I always try to make sure we’re going to use these, and we’re—as you all are, too—in phase I clinics. So, we throw those options on the table, as well. Now we’ve got reintroduction, we’ve got 2 drugs with approval and survival, and we’ve got trials, which is what we’re in the business of doing. We kind of want to get them all in, right?

Transcript Edited for Clarity