Van K. Morris, MD: [00:00:00] Thanks Allen for for having me and letting me represent our team of investigators who reported the results from the NRG-GI005 (COBRA) trial. This past weekend at the ASCO GI Symposium in San Francisco, this is a phase two trial that evaluated the role of circulating tumor DNA as a predictive biomarker for adjuvant chemotherapy in patients with low risk stage two eight colon cancer.
This was also the first trial that the NCI ever supported evaluating circulating tumor DNA as an integral biomarker for any solid tumor type. So we all recognize that in colon cancer, but really in solid tumors in general. That the detection of circulating tumor DNA is a highly sensitive biomarker for identification of kind of micro metastatic mineral residual disease.
And what this means is that when a patient has [00:01:00] completed definitive therapy for their colorectal cancer and has detectable circulating tumor DNA there. is this is a biomarker associated with really inevitability that cancer is still around and is going to recur. Whereas on the other hand, when patients, especially over time have negative circulating tumor DNA results serious serially there’s a high likelihood that the cancer will never recur.
So we all very much recognize the power of this tool for as prognosticating, whether or not a patient’s colon cancer is going to come back. What has not been fully validated to date really is how we can use this information to guide treatment decision making. Now, several years ago the Australian group led by Dr.
Jeanne Tie out of Australia published the dynamic study in the New England Journal of Medicine. This was a phase two trial that looked at the use of circulating tumor DNA. As a tool to justify de [00:02:00] escalation of treatment. In patients with stage two colon cancer and what they showed here in the dynamic study is that that when you, that relative to standard kind of practice patterns, when you uh, use, when you identify patients who are at low risk for recurrence, according to a negative circulating tumor DNA status, that in general, this is associated with less use of adjuvant chemotherapy and that this does not compromise use.
Survival outcomes when you select out negative ctDNA statuses as a justification for not proceeding with adjuvant chemotherapy. The flip side of this is what do you do with a positive result? And to date in patients with colon cancer, we have not had yet a prospective clinical trial, which has.
Looked to see the role of of circulating tumor TNA as an integral biomarker in seeing if this is effective and identifying patients who would [00:03:00] otherwise be at high risk for occurrence and benefit for. So this is why we did the NRG-GI005 (COBRA) trial. This was a phase 2 trial which evaluated patients with the pathologic T3N0M0, so stage 2A colon cancer, that kind of according to standard practice patterns was determined to be low risk for recurrence and based on the discretion of the treating medical oncologist, these patients, the participants in this study according to standard practice patterns with the appropriate for active surveillance and would not be recommended adjuvant chemotherapy.
So these are the T3N0 patients with all low risk features that oncologists feel comfortable just proceeding with active surveillance. And on this trial, patients were randomized in a one to one fashion to either standard of care, which is active surveillance. And in this setting, blood was banked was collected and banked at baseline, in the post operative setting.
And then [00:04:00] six months later to assess, changes in ctDNA patterns over time. And then in the Other, the experimental arm, patients were randomized to receive or patients were directed to receive chemotherapy according to their ctDNA status. If prospectively, in the experimental arm, the patients were found to have detectable circulating tumor DNA, they were deemed at high risk for recurrence and recommended treatment with six months of either full Fox or K box adjuvant chemotherapy if in this experimental arm ctDNA was tested prospectively and there was no ctDNA detected again, they were deemed low risk for occurrence and proceeded on to active surveillance.
We use the garden lunar assay as the ctDNA assay of choice. This is a tumor agnostic assay, which incorporates both genomic somatic mutation calls as well as an epigenomic. colorectal cancer specific methylation [00:05:00] call as well as a combined tool for detection and determination of ctDNA status.
And the primary endpoint for this study for the phase two portion was to evaluate a clearance at ctDNA clearance of ctDNA at six months among patients who had detectable ctDNA baseline between the clearance Or between the chemotherapy arm and the surveillance arm, and our hypothesis was that we would see greater clearance in the patients who are randomized to chemotherapy after six months relative to those who had proceeded to active surveillance again among the patients who had detectable ctDNA baseline.
So for the phase two analysis, we analyzed the first 16 patients who were ctDNA positive at baseline. And what we saw were that there were seven patients who are randomized to the standard of care [00:06:00] active surveillance arm. And there were nine patients who were randomized to the chemotherapy to receive treatment with chemotherapy.
And among the patients who were treated. With chemo or who are randomized to the chemotherapy treatment or we saw clearance in one of nine. And among the the patients who are randomized to active surveillance, there was clearance in three of seven. So we observed a 43 percent clearance rate with surveillance and 11 percent clearance rate with chemotherapy.
And because this, the. Because of the one sided p value exceeding the predefined specification for futility, by protocol we were not able to reject our null hypothesis and had to end the trial early due to futility. So in we did our conclusions from this were that we did not observe using the selected ctDNA assay an [00:07:00] improvement in ctDNA clearance with chemotherapy relative to surveillance among patients with a low risk stage 2a colon cancer who had detectable or who had detected ctDNA at baseline.
It was striking to us, however, that the enrollment continued to persist over the course of trial conduct despite the COVID 19 pandemic, despite multiple ctDNA assays becoming commercially available over the course of this study, and to us, this signified continued interest among patients and oncologists alike in enrolling onto ctDNA trials, given the fact that we don’t have really yet have level one evidence to know, how best to utilize this powerful technology.
I think that there will be future trials. I think the technology is here to stay. We all recognize the power of CT DNA and the clinical management of oncology. And I think that there will be more and more trials which come after this. And [00:08:00] there definitely is more research that needs to happen.
It’s important, given how quickly these technologies are evolving, that we You know that as we conduct these trials in the future, we continue to collect blood on the side, so that we can, continually reevaluate our endpoints for clinical trial conduct given the rapid advances and accelerating kind of sensitivity and assay performance of these CT DNA technologies.