Roundtable Discussion: Kundranda and Participants Review First-line and Later-line Therapies in CRC

Madappa Kundranda, MD, PhD (Moderator)

Gastrointestinal Medical Oncologist

Banner MD Anderson Cancer Center Clinic

Gilbert, AZ

PARIKH: I think my biggest concern would be the neurotoxicity with oxaliplatin; the time to recurrence isn’t that great. I’m almost suspecting that oxaliplatin didn’t work at all. I would add a biologic to this regimen to try and maximize response up front.

KUNDRANDA: I think that is certainly the rationale that most [use]. The 6-month rule that we typically use…in terms of platinum sensitivity, most of that rule comes from our patients with ovarian cancer.

In this case, with somebody who’s had such a short disease-free interval and never been exposed to irinotecan, it’s certainly very reasonable. [As is] adding a biological to that. The significance of NGS in the up-front treatment of biological agents…when we think about NGS, I think all of us do that. Some of the labs automatically reflex to at least microsatellite instability [MSI] testing, and I’ve seen that. Some of our labs tend to do more of an extensive panel as we have seen, which is the expanded KRAS panel, along with the MSI testing.

Typically, when you have a patient with a new diagnosis of metastatic colon cancer or rectal cancer, do you normally just get one of the comprehensive NGS panels or do you get more of the limited [panel], NTRK fusions, KRAS, MSI, and HER2 now because of the therapeutic options that we have in that subset of patients?

KAHN: I find it easier to get everything done at once in 1 setting. For example, with FoundationOne [testing], you can get everything [simultaneously] and it’s much easier than ordering individually.

KUNDRANDA: Has anybody else got a different approach? Because previously, we’ve had instances when we would just get a limited panel; once the patient progresses to first line and second line, that’s when they would get the more comprehensive panel. Or does everyone go for the comprehensive panel up front?

SUD: I agree with Dr Kahn. I also get the whole comprehensive panel, with a KRAS mutation panel, sent up front. All the tissue is not an issue, like the amount of tissue [the way we run into] trouble with lung cancer when we do piecemeal testing. But in this, that’s not as much an issue, but it’s still more convenient to get all the information together as you get started on treatment.

KUNDRANDA: I agree. That’s been one of the shifts we’ve seen across the board, because tissue does become the issue. When I biopsy the liver to get tissue for molecular profiling, now I just label it “molecular profiling”—I don’t need the whole panel of all the CD testing done…. It’s worthwhile to get it up front for a multitude of reasons.

One is obviously to find the best option for these patients but also to ensure that if you need to retest these patients—[for] a clinical trial or the like—you already have tissue that’s banked and you haven’t exhausted those. That has been helpful in colon cancer, and I think most of the cancers, in trying to do this up front.

KUNDRANDA: Most of us would look at it and say this would be a patient you would absolutely switch therapies on, because this patient has radiological progression and that makes it a lot easier. You have clinical progression as well.

The question becomes—and [I’ve] run into this a multitude of times, wherein if you have questionable clinical progression; radiologically, things are stable; and you have biochemical progression—what do you typically do in that context?

Do you switch therapies or do you continue with the same agent, knowing full well that the biochemical progression could probably have a lead time compared with radiological progression? What is everyone’s comfort level in regard to switching therapy based on biochemical progression?

YOO: The carcinoembryonic antigen [CEA] fools me every time. It’s concerning to see ongoing increase, but there are a few times I kept doing the CT scan and I saw [almost] no measurable change.

Often I’m having a discussion with a heavily treated patient, so usually I go with the CT scan and measurable disease changes, and I tend to biopsy and confirm.

KUNDRANDA: I completely agree. This is where we’ve all been burned: when the patient is getting anxious because the patient’s following their CEA from 6.9 ng/mL to 7.1 ng/mL, then drops to 6.8 ng/mL, and then goes back to 7.2 ng/mL.

The patient thinks this [is] progressive [disease]. I see this in my clinic at least once a week. But you also have the true biochemical progression where you see a CEA going from 40 ng/mL to 80 ng/mL; but radiologically the patient is stable, maybe some questionable clinical progression.

The only exception…wherein I have switched therapies is when I have biochemical progression with absolute clinical progression—there’s weight loss, there’s new pains that I cannot explain for any other reason…

Most of these patients do have progression. Even in these patients, if you wait the additional 3 or 4 weeks and you restage them, they will have radiological progression.

PARIKH: Is there a certain number [or percentage increase of CEA] you use when you are determining progression?

KUNDRANDA: No. Unfortunately, it depends on what their baseline is. Some of these patients are nonsecretors or they’re just minimal secretors. I’ve had patients walk in with a CEA of 1000 ng/mL and doing well; I’ve had patients with a CEA of 25 ng/mL crashing and burning. The CEA by itself does not give us an idea in terms of the burden of disease or the rate of progression, although the trends do help.

PRASAD: Sometimes, the only thing [changing] is the rate of increase of CEA, maybe within a week or 2, if it doubles, that may be [progression]. Sometimes patients get symptomatic, with more pain and maybe ascites, and sometimes CT scans don’t show peritoneal carcinomatosis so well. In those cases, maybe we’ll have to plan on a change of treatment if we think they’re progressing despite treatment.

KUNDRANDA: That’s a very good point because that’s where your clinical progression comes into play. Combining the clinical progression with the biochemical progression does make a difference.

KUNDRANDA: A majority went with irinotecan with an anti-EGFR inhibitor. [Others said] to rechallenge the patient because the patient was [on] capecitabine and bevacizumab. Would you rechallenge the patient with FOLFIRI or would you rechallenge the patient with FOLFOXIRI with bevacizumab?

That was the question because the patient had this progression after about 10 months. It certainly is reasonable. But, keeping in mind that the patient has residual neuropathy, continuing with the platinum therapy is going to be a low return on investment. With the irinotecan/anti-EGFR, the question is, would you use an anti-EGFR in the setting of a BRAF mutation? I think we have enough data to indicate that if the patient has a BRAF mutation, using an anti-EGFR is probably not going to be beneficial. If anything, it might be detrimental. In this scenario, going back to rechallenging the patient with FOLFIRI plus bevacizumab [Avastin] would be reasonable. Switching therapy to TAS-102 [trifluridine-tipiracil (Lonsurf)] with or without bevacizumab…is [a good] way to do it for a multitude of reasons, at least based on the data that we have. Using regorafenib [Stivarga] would also be reasonable. These would be the 3 options at this point.

KUNDRANDA: In a patient who’s had FOLFOXIRI for [a while] and had toxicities and now is on capecitabine plus bevacizumab maintenance, would there be any consideration in switching therapies to something less myelosuppressive? Or at this point, would you say getting more bang for your buck in the context of getting more for cytotoxic reduction is the way to approach this?

MUKHERJEE: We’ve learned how to manage neutropenia infections. I think neurotoxicity is the one that we mainly find challenging.

KUNDRANDA: Absolutely. If you have a patient [and], in this case, go back to FOLFIRI/bevacizumab, would you start off with a dose reduction in these patients?

MUKHERJEE: It depends upon the level of toxicity. If a patient has a fair burden of neurological toxicity, yes I would. If the patient is OK, then I would start and see how it goes and then reduce it as needed.

KUNDRANDA: If you do end up having myelosuppression—let’s just say mainly the neutropenia, and the rest of it is more or less manageable—in regard to having growth factor support [authorized], are you having any challenges…in a patient who has had dose reductions?

Have you run into the challenge of getting either Neulasta [pegfilgrastim] or Neupogen [filgrastim] in these patients if you run into myelosuppression, whether you dose reduce it or not?

PARIKH: No, it’s approved.

KUNDRANDA: I’ve had issues where the patient has an absolute neutrophil count of 900 and I still cannot get [growth factor support]. I think it’s probably an insurance thing, but… that’s not an issue that you have had in general?

PARIKH: There is one insurance that we have that will require a fever with it. Fever is easy to document.

With the availability of TAS-102 and the data out there, do you still use regorafenib?

KUNDRANDA: When you think about the survival benefit between TAS-102 and regorafenib, they are comparable. I don’t think most practices use TAS-102 by itself, and we do not have a direct comparison in terms of TAS-102 vs regorafenib.

Do any of you typically use TAS-102 by itself, or have you had any issues in terms of having bevacizumab approved with TAS-102?

YOO: The insurance denied 2 times because they were saying the patient progressed on bevacizumab, so why do you have to use it again?

They’re just going for FDA approvals, and there’s no approval. It’s not strongly suggested by National Comprehensive Cancer Network guidelines.

KUNDRANDA: I haven’t run into that issue.

KUNDRANDA: Are any of you familiar with the data that we have with fruquintinib [Elunate], which is an oral anti-VEGF? The [trial] started out of China [NCT02314819]. Fruquintinib is an anti-VEGF oral agent, hits the VEGF1, VEGF2, and VEGF3 pathway. The survival data was impressive. The overall survival was about 9 months in these patients who were refractory.¹

However, the caveat to that study was the fact that…in the Chinese patient population, none of them were exposed to an anti-VEGF. I need to take that with a grain of salt when I think about it, because this was fruquintinib vs placebo in these patients. We currently have a study [of fruquintinib] that’s open at multiple sites, and we should have some of the data pan out very soon.

More than likely, this would be another agent that we would have the refractory setting and certainly something that I think is worth mentioning, although we don’t have the data yet.

_REFERENCE

_{1. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855}