To watch Dr. Arvind Dasari discuss the NRG-GI008 presentation with slides, Click Here!
NRG-GI008 (CIRCULATE-US) is really seeking to answer the question. Can circulating tumor DNA be used to guide therapy for lower risk stage III colon cancer? Now we know that circulating tumor DNA has really been a game changer in terms of how we learn more about not only the genomics of the cancers that we have but if there's minimal residual disease still left in the body. But of course, part of the problem with knowing if there's molecular presence of residual disease, but nothing that we see on a CT scan is that we really don't know what to do with that. In other words, if somebody is ctDNA negative, could you use that information to maybe prevent people from having to receive colon adjuvant chemotherapy?
Conversely, if somebody is ctDNA positive (circulating tumor DNA), is there a way to give more aggressive adjuvant chemotherapy and therefore reduce the risk of recurrence or the rate of recurrence? And so NRG-GI008 (CIRCULATE-US) is a study that looks at both of those groups. So if you have low risk stage III colon cancer as defined having either T 1-3 disease or N1 disease.
So the compounds that we're gonna utilize in this clinical trial and I in NRG-GI008 (CIRCULATE-US) are really just chemotherapies that we traditionally use. So when you look at the ctDNA, negative cohort, those are patients that postoperatively have no detectable ctDNA the standard of care.
There is FOLFOX or CAPOX adjuvant chemotherapy traditionally given for around three months based on the idea of collaboration but of course the comparator, there is no therapeutic agent is surveillance with serial testing. When you look at the ctDNA positive cohort, again, the standard of care is to give those patients full FOLFOX or CAPOX in this case, because they're such very high risk factors for occurrence.
The total duration is six months, but then when you look at the investigational arm, that's the full fear arm. That's the triplet chemotherapy really trying to determine is double chemotherapy. Or would escalation of adjuvant chemotherapy with a three drug regimen, FOLFOX be more effective at preventing recurrence because we know that those patients that are ctDNA positive postoperatively are the ones that are most likely to recure.
So for patients to be included in NRG-GI008 (CIRCULATE-US) they have to have lower risk stage III colon cancer. What does that mean? That means that patients are gonna have T 1-3 disease and they're gonna have N1 disease. This includes N1C which means tumor deposits however, those patients that are excluded are patients with rectal cancer with T4 disease which would be considered a higher risk factor.
Patients that have N2 disease, which means that many node are involved and would also be considered to be a higher risk factor otherwise in patients have lower risk stage III colon cancer. They really should be considered for this study as it answers a really critical question using a very novel technology.
T4 and N2 disease is excluded. Patients are tested for ctDNA. And if they're ctDNA negative, they get randomized to standard of care chemotherapy, which they would normally receive or observation. With serial testing and if patients are ctDNA positive, then they're randomized to receive standard of care chemotherapy, which would be FOLFOX or CAPOX or an escalation of colon adjuvant chemotherapy with FOLFOX. Now, if patients have, high risk stage II disease or very high risk stage III disease, where they get outside testing and that testing is positive, they're also eligible for that arm. And so this study, when completed will help answer the question, can we utilize ctDNA to guide therapy for our stage III patients with colon cancer in terms of management.
I think we're mainly at the beginning at the forefront of kind of having data in this setting. I think with, stage II, colon cancer, there's actually been recent data presented at ASCO 2022, looking at the utilization of ctDNA and outcomes. When ctDNA is used to guide therapy and that study was presented at ASCO several months ago.
But in terms of stage III colon cancer, I mean, we have small subsets of data that we can look at and it suggest that ctDNA negative, the rates of occurrence are quite low. If your ctDNA positive, the rates of occurrence can be quite high but I think that this will not only be number one, get a bigger sample set to tell. How these patients do what the NA, what their natural history is, but then number two, can an intervention be utilized using the ctDNA, to improve the disease-free survival dfs rates of our patients, or in some cases, prevent them from the toxicity of adjuvant chemotherapy.
So we expect the accrual to happen, you know, really over the next two to three years. Obviously we would love for this study to accrue even faster than that. And then there's a little bit of time after a study completes accrual, where we just have to wait for enough events to occur, to really get an idea of what the impact of the intervention is. I think in the meantime, what you'll see is additional small subsets of data come out to help us better understand the use of ctDNA or even the results of ctDNA and how they impact patients. We're also not the only country that are performing these types of studies. And so I think you'll see additional data come out of the Japanese groups and the Australian and European groups, as they all have those studies ongoing as well. So I think really over the next couple years, we're gonna have a real treasure trove of data to look at and we'll have a much better idea about how to utilize this type of technology.