Cumulative clearance rates of ctDNA per ACT reception


Mark Lewis, MD: It’s really interesting. This shows me why adjuvant chemotherapy was an acceptable practice for years before the ability to demonstrate the elimination of MRD [minimal residual disease]. Here, if I understood [Masahito] Kotaka [MD, PhD,] correctly, look at what happened between postoperative week 4 and week 24 to the signals in the ctDNA [circulating tumor DNA]. Clearance, of course, [is] ranging from positive to negative. You can see that with the receipt of adjuvant therapy, the rate of this clearance was 68%. Fascinatingly, you also found clearance in 10% of patients who were not receiving adjuvant chemotherapy. I’m curious to hear your speculations as to why this might be. For me, it comes down to the cart problem. When I first started thinking about adjuvant chemotherapy, I thought of it as an ethical issue. The trolley problem has you where, if you act to save some people, you could hurt 1 person. I’m not trying to exaggerate, but these chemotherapy drugs that we give in this exact scenario may have irreversible toxicity. I was literally taught on day one of the fraternity to have the utmost respect for oxaliplatin. My faculty taught me that if you give this in the wrong amounts or for the wrong duration, the patient can have permanent nerve damage. In fact, there was a side conversation at ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] this year titled “Oxaliplatin de-escalation”.

What I mean is there are 2 things we are trying to do here. We’re trying to make sure that people who really need adjuvant chemotherapy get it, and it’s pretty nice if it works the way we hope it will, that we can then quantify the disappearance of their MRD signal. But it’s also, in its best embodiment, potentially likely to help us figure out who doesn’t need adjuvant chemotherapy at all. And I will keep a close eye on this particular part of the VEGA study. Again, these will be the postoperative negative ctDNAs [patients], which will then be randomized to observation. So watch this space. What are your takeaways here?

Stacey A. Cohen, MD: I also looked at that 10% of people who erased their cDNA and found that very interesting. I would like to understand how we can do less and get better results from everything. Wouldn’t that be awesome? I think it also has to do with the fact that we implicitly consider how this exclusive testing is done, but the reality is that this is also dynamic. You’ve already referenced 3 different studies setting the context for this that use 3 different tests, each with their own quirks. I think part of the problem we’re going to have going forward with ctDNA is that it’s a technology, and technology isn’t fixed, it changes, always with a bit luck for the best, but our studies are snapshots in time with the test of the moment. So you’re wondering if that means there’s a threshold where we get false positives? Quantitatively, I’d like to know, are we seeing very low-level positives that go away on their own? Or did these patients have high levels of detectable ctDNA that really disappeared? I think there will be so many ways to look at this data, since one of the benefits of Signatera is that you can get a quantitative readout in addition to the qualitative yes/no, positive/negative readout. I think that will be a very interesting level of information to apply to this question of examining the benefits of chemotherapy.

Mark Lewis, MD: Beautifully said, and you’re absolutely right. Of the 3 studies I cited as background, it was only the [Thomas] Reinert, [PhD,] 2019 study that used the same proprietary tumor-informed test used in GALAXY. There is therefore a great deal of heterogeneity in the performance characteristics of these different measures. In fact, I know with this particular test there is a lot of caution in not getting your first point too close to surgery because the invasiveness of the operation releases a lot of cell-free DNA which can confuse the signal. There, you might think that would be a false positive. It is therefore fascinating to see how this space will evolve. And you’re right, it’s going to happen I think in parallel with a lot of the products that are becoming available for oncologists to use in their patients.

Transcript edited for clarity.