Trials Focused on ctDNA in Colorectal Cancer


An expert panel discusses clinical trials focused on circulating tumor DNA in guiding treatment selection in colorectal cancer.


Cathy Eng, MD, FACP, FASCO: I know everyone’s an expert on circulating tumor DNA [ctDNA], but I also know 2 of you have some big trials regarding circulating tumor DNA. So, can you tell me how you incorporate it in your current treatment landscape? I know you have your Stand Up to Cancer study, and obviously, you have your big phase 3 CIRCULATE-US (NCT05174169) trial, as well. So, do you care to comment about what this can mean in regard to the certain patient populations you’re looking at? I know you mentioned it very briefly earlier, but maybe our audience may not be aware.

Aparna Parikh, MD: Sure, yes. So taking a step back to answer the first part of your question of how I’m incorporating it routinely now. The patients where I feel very comfortable—and we don’t have the COBRA trial (NCT04068103) open—so, I think for the stage II low-risk patients, those are patients where I feel very comfortable, if they end up being ctDNA-positive, escalating care. I think the take-home message for me, at least with all the data we have to date, is I’m not yet comfortable in a patient—even for a stage III patient who is ctDNA negative—I don’t think we have the sensitivities yet to really feel good about de-escalating care. I think some of the data we saw from the Japanese group is provocative from the recent Nature Medicine paper with only 16 months of follow-up still. But showing that patients who were ctDNA-negative had less of a benefit for adjuvant chemotherapy. So, certainly provocative data and large data, but not yet.

Cathy Eng, MD, FACP, FASCO: We’re talking about the GALAXY study.

Aparna Parikh, MD: The GALAXY trial, yes. From GALAXY exactly, but not quite yet ready to do that off of a clinical trial. And then so, obviously, COBRA [NCT04068103] trialis looking at stage II and I’ll let Dr Dasari talk about CIRCULATE-US, which is an amazing study and I’m looking forward to seeing those results come in. And then our study is looking at postadjuvant and chemotherapy. So, standard of care, stage III low-risk, high-risk, CAPOX [capecitabine and oxaliplatin], FOLFOX [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] and the clinician’s choice of treatment.

And then if you’re a ctDNA-positive postadjuvant and chemotherapy patient, you get randomized to active surveillance and surveillance is a little bit more stringent than the NCCN [National Comprehensive Cancer Network] guidelines would otherwise recommend. So, it’s 3 months of CT scans vs FOLFIRI [leucovorin calcium (folinic acid), fluorouracil, and irinotecan). And if you have a biomarker, we have several biomarker groups that are exploratory subgroups. If you’re positive and are BRAF-altered, then you can get the BEACON regimen [encorafenib, cetuximab, and binimetinib]. We’re doing the triplet, despite the toxicity, but given higher response rates to give in the adjuvant setting. So, encorafenib, binimetinib, and cetuximab for the BRAF V600e patients we’re giving 6 months of atezolizumab if you’re MSI [microsatellite instability] high, ctDNA-positive after. And then, this is pre MOUNTAINEER (NCT03043313), so Herceptin, Perjeta for the HER2 [human epidermal growth factor receptor 2] patients.

Cathy Eng, MD, FACP, FASCO: And I think it’s really important what you just emphasized about how diverse the role of circulating tumor DNA can be. Not only looking for minimal residual disease [MRD] but looking at molecular marker analysis, as well. And now you have a large phase 3 trial in the stage III setting. So, Dr Dasari could you please comment on your study that you’re working on?

Arvind Dasari, MD, MS: Yes, absolutely. This was in many ways a labor of love, so I’m happy to chat about it. So, the current approach for patients with stage III colon cancer is everybody gets adjuvant chemotherapy. But what we know is that we’re only benefiting probably about 20% to 25% of these patients, with the rest of the patients probably not requiring chemotherapy because they never were at risk of developing recurrent disease and the rest developing recurrent disease in spite of doing current standard of care adjuvant chemotherapy. So, the CIRCULATE-US trial is trying to address both these questions.

And so, patients with stage III colon cancer would be enrolled and evaluated for minimal residual disease postoperatively. And patients who are ctDNA-negative, or minimal residual disease-negative would be randomized to 1 of 2 arms: immediate adjuvant chemotherapy vs delayed adjuvant chemotherapy where they would undergo serial surveillance with ctDNA and then be offered adjuvant therapy if and when they turn MRD- or ctDNA-positive. On the other hand, if these patients have detectable ctDNA or detectable MRD after surgery, then the question being asked is, how can we do better compared to the current standard of care adjuvant chemotherapy? So, they would be randomized to a doublet of fluoropyrimidine plus oxaliplatin vs a triplet with the addition of irinotecan.

Cathy Eng, MD, FACP, FASCO: So FOLFIRINOX [leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin].

Arvind Dasari, MD, MS: FOLFIRINOX, yes. And the study is open and rolling, so this is what we’ve discussed. So far both COBRA and CIRCULATE-US trials are in the immediate postoperative setting. And Dr Parikh nicely outlined what if patients turn MRD-positive after completion of adjuvant therapy during surveillance test initiation of systemic therapy early on and it changed the natural history of these patients? So, together, I think this body of evidence that’s building and hopefully, we’ll read out soon, will change how we approach the care of these patients.

Cathy Eng, MD, FACP, FASCO: And if I’m correct, Rona Yaeger, MD, at Memorial Sloan Kettering Cancer Center has an adjuvant BRAF trial that’s opening up shortly. So, obviously the role of circulating tumor DNA will also be involved in that treatment schema.

Michael Foote, MD: Yes, that’s exactly right, yes. We have a couple of studies that look at ctDNA after resection. There’s 1 for mismatch repair deficient tumors as well that Yelena Janjigian, MD, does to evaluate patients who didn’t get immunotherapy before. And if they’re positive, they get immunotherapy afterward. And then the Dr Yaeger study is great, too.

Cathy Eng, MD, FACP, FASCO: Wonderful.

Transcript edited for clarity.

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