Dr. Cathy Eng:
Welcome to The ASCO Post Roundtable Series on Updates in Colorectal Cancer. I'm Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center. Joining me today are two of my colleagues.
Dr. Arvind Dasari:
Hi. I'm Arvind Dasari. I'm a medical oncologist in the Department of GI Medical Oncology at MD Anderson Cancer Center.
Dr. Smitha Krishnamurthi:
Hi. I'm Smitha Krishnamurthi. I'm a medical oncologist, GI oncologist at Cleveland Clinic.
Dr. Eng:
We're discussing recent updates in colorectal cancer and integrating these new developments into four case studies. Our first installment will focus on the role of circulating tumor DNA in early stage colon cancer. Case one, the role of circulating tumor DNA. This is a 48-year-old woman with a history of right-sided adenocarcinoma status-post right hemicolectomy. Preoperative scans did not demonstrate any evidence of metastatic disease and her CEA was within normal limits. Post-op pathology revealed a T3N0 moderately differentiated adenocarcinoma, 0 of 28 lymph nodes positive without any evidence of perineural or lymphovascular invasion, and widely negative margins. Immunohistochemistry revealed intact mismatch repair protein expression, so she's MSI stable. She's the mother of three school-aged children and plays the violin. Circulating tumor DNA or circulating tumor DNA assay was sent postoperatively and is read as negative. She presents to your clinic now four weeks after surgery asking about the next best therapy for her situation. Dr. Dasari, would you like to explain a little bit more about your thoughts on this case?
Dr. Dasari:
Thank you, Cathy. So in summary, this is a young patient with a low-risk stage II colon cancer. And there are some really compelling data about the use of ctDNA, determining the risk of recurrence in these patients and how we can use this information to make treatment decisions regarding adjuvant therapy. So the DYNAMIC trial enrolled patients with stage II colon cancer who had R0 resection without evidence of a metastatic disease on scans. And patients were randomized 2:1 to ctDNA-guided management, where if they were ctDNA-positive, would get adjuvant chemotherapy. If they were ctDNA-negative, would be placed under observation, vs standard of care management where they would receive adjuvant treatment decisions based on conventional clinical and pathological criteria. The primary endpoint was relapse-free survival at 2 years, and a key secondary endpoint was proportion of patients receiving adjuvant chemotherapy in these two arms.
Looking at the results of this trial, overall, the proportion of patients who received adjuvant chemotherapy was lower in the ctDNA-guided arm, approximately half of the standard management arm, and the recurrence-free survival outcome actually met the primary endpoint boundary. So this was a non-inferiority trial with the non-inferiority margin of -8.5%. And the difference between the two arms was above this boundary, therefore the trial was positive overall. The hazard ratio of recurrence-free survival between the two arms was 0.96 and this is after a median follow-up of 37 months.
Now, there are still several unanswered questions in the management of patients with stage II colon cancer and the use of ctDNA. For instance, in the DYNAMIC trial, while patients who were ctDNA-negative and clinically low-risk did relatively well, patients who were either ctDNA-positive or high-risk and ctDNA-negative, still had a risk of recurrence that was higher than the patients who were both ctDNA-negative and clinically low-risk.
So there are ongoing trials attempting to address this question of, how can we better prognosticate patients with stage II colon cancer utilizing ctDNA status? The COBRA trial is enrolling patients with low-risk stage II colon cancers, stage IIA, who deem suitable for active surveillance by their physicians. And they would be randomized to standard of care approach where they would undergo surveillance vs ctDNA as a directed therapy, where if they're ctDNA-positive, they would get adjuvant chemotherapy where a fluoropyrimidine plus oxaliplatin. And if they're ctDNA-negative, undergo active surveillance. This is a phase II/III trial and is currently enrolling patients throughout North America.
Dr. Eng:
Dr. Dasari, do you mind commenting on, for somebody that's just read the publication from Dr. Tie's group regarding DYNAMIC and now with COBRA still enrolling, what is the advantage for a patient to participate in COBRA with stage II disease given some of the data that's come out of DYNAMIC for a better understanding of the difference between the two trials?
Dr. Dasari:
Yeah, indeed. Diving a little deeper into the data presented by Dr. Tie and her group at ASCO, what we see is that it's not just the ctDNA status that is relevant for instance patients who are ctDNA negative and low risk, overall seem to do really well. But patients who are ctDNA positive or who have histopathological features suggest above high risk, their risk of recurrence seems to be still higher. So it's clear that while these data are very, very compelling, we still have several unanswered questions about how do we best prognosticate the risk of recurrence in patients with stage II colon cancer? And that is where completing trials like the ongoing COBRA trial would be incredibly valuable. Specifically with regards to the COBRA trial, the question that it is asking is in patients who are thought to be low risk clinically, what would the additional benefit of looking at ctDNA be in these patients and help address this question to a certain extent?
Dr. Eng:
Thank you so much for going over that literature and I think we want to expand upon the same case a little bit further. So just a friendly reminder, this is a 48-year-old woman with a right-sided colon carcinoma status-post right hemicolectomy; preoperative scans for unremarkable. Her CEA was within normal limits. Her post-op path was a T3N1. In this setting now, with 1 of 28 lymph nodes though so we're changing the scenario a little bit, without any paraneural or lymphovascular invasion and widely negative margins. Once again, MSI stable with intact mismatch repair protein expression, young mother with three school age children and plays the violin. Now her tumor informed circulating tumor DNA assay sent postoperatively is positive. She presents to your clinic now 4 weeks after surgery asking about the next best therapy for her situation. So now Dr. Dasari, can you elaborate upon changing now to the stage III setting?
Dr. Dasari:
Yeah, so the key differences between this case and the prior one being that the patient has stage III colon cancer and also ctDNA positive, so what are the implications of these findings? Now, compared to stage II colon cancer where the default would perhaps be to not do adjuvant chemotherapy, the current guidelines recommend that we do adjuvant chemotherapy in everybody with stage III colon cancer. Now, I want to pause here and maybe pivot to the results of the CIRCULATE-Japan trial that were presented at GI ASCO earlier this year. As a reminder, this is a large effort on-going in Japan having components of a screening trial that is enrolling patients with a colon and rectal cancer who are screened for ctDNA. And then based on those results, they are enrolled onto interventional trials. The data that were presented at GI ASCO were from the screening effort presented as an observational cohort.
A total of about close to 1,500 patients or a little over were enrolled onto the trial and these included patients from stage I through stage IV, although the vast majority of patients had stage II and stage III colon cancer as to be expected. At GI ASCO results from about 1,000 patients were presented and the first set of data that we should look at would be disease-free survival outcomes by postoperative ctDNA status at 4 weeks. And this was in patients with stage II and stage III colon cancer and disease-free survival was presented at 6 months and 12 months as landmark analysis. What they found was that patients who were postoperatively ctDNA negative did really well with 6-month DFS being around 98% and the 12-month DFS being around 95% as compared to those who are ctDNA positive in whom the DFS dropped to 73% at 6 months and about 55% at 12 months, but the overall hazard ratio being about 13%.
So they also looked at additional outcomes so we know that these patients who are ctDNA positive at 4 weeks postoperatively do poorly. Well, how does the delivery of adjuvant chemotherapy change the outcomes of these patients? So in these results, what they found was that the 6-month DFS changed based on the ctDNA dynamics, that is how did the ctDNA status change from 4 weeks to 12 weeks? And patients who were ctDNA negative and continued to be negative did well. So as did the patients who were ctDNA positive and then turned to ctDNA negative with adjuvant chemotherapy. And this was in contrast to patients who were ctDNA positive and continued to stay positive after completion of adjuvant chemotherapy. For instance, looking at the difference in outcomes of patients who are positive to negative vs positive to positive, the hazard ratio of DFS was about 52 with a median follow up of about 6 months.
So clearly, what this suggests is that patients who are ctDNA positive after surgery tend to do poorly but we are able to change their outcomes by delivering effective adjuvant chemotherapy if we're able to change their ctDNA status from positive to negative. Building on this, the ongoing CIRCULATE-US trial or NRG-GI008 trial is attempting to kind of define two things. Firstly, based on postoperative ctDNA status and stage III colon cancer patients who are at low risk. If they are CT DNA negative, can we deescalate adjuvant chemotherapy? These patients would be randomized to immediate adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin vs continued surveillance with ctDNA evaluation every 3 months. And if and when these patients turn ctDNA positive, then they would get adjuvant chemotherapy which I'll go over in just a second.
In patients who are postoperatively ctDNA positive, the question that is being asked is what is the most effective adjuvant chemotherapy for these patients? So these patients would be randomized to current standard of care that is fluoropyrimidine plus oxaliplatin for 6 months vs the addition of irinotecan to this combination, so FOLFIRINOX, for 6 months. Patients who turn ctDNA positive during surveillance from the prior cohort would also be enrolled onto this cohort. And of note, since the use of ctDNA evaluation is fairly established at this point, patients who are otherwise not eligible for this trial... So there is patients who are stage II or high risk stage III colon cancer if they're ctDNA positive are also allowed to enroll onto this trial. So this trial is just started and rolling throughout the NCTN Network.
Dr. Eng:
So I want to make sure we give credit to Dr. Dasari which he's not giving credit to himself for. He is the PI for this trial and is leading this effort with Dr. Christopher Lieu. I did have one question, Dr. Dasari, I'm just curious though between COBRA which utilizes Guardant if I'm correct, and then CIRCULATE if I'm correct is using Signatera. The platforms are a little bit different, do you think we really know which platform may be the best approach now or do you feel that they're fairly equivalent based upon the information we have thus far? Obviously, these are wonderful studies that we should be enrolling to but I was just curious.
Dr. Dasari:
Yeah, great question and I think that's a huge unmet need in terms of trying to compare these different assays that are available because there are several others that are going to be available or are in development. So standardization is a key issue and that's a topic of discussion so as of now there are no head-to-head comparisons. But until we have those data, perhaps the best way to make the decision would be whether we want to use a tumor informed assay, for instance Signatera as a tumor informed assay, where you need the patient's tumor tissue to design the assay that would then be used to detect ctDNA vs the Guardant assays which are tumor tissue agnostic and only require plasma.
So how do we kind of try to make that determination? Well, it depends on how quickly we want those results back and whether we have access to tumor tissue while sending these assays. For instance, in the case of say, rectal cancer, we're increasingly moving towards TNT or total neoadjuvant therapy with a good proportion of patients having complete clinical response. We may well end up using assays such as Guardant that did not have requirement of tumor tissue.
Dr. Eng:
That's a great point. Thank you so much. And Dr. Krishnamurthi, I was just curious... following this presentation at ASCO, I'm wondering if a lot of your patients are inquiring now about the role of circulating tumor DNA and I presume you're enrolling to these clinical trials if the patient qualifies.
Dr. Krishnamurthi:
Yes. Definitely very excited to open CIRCULATE, we're in the process of opening it and we have been enrolling to COBRA and I think the case presented of the low risk stage II patient would've been ideal for COBRA so we are encouraging everyone to go that route. But as you point out, patients are asking about these tests and so I do talk to them about the Signatera which I think has been developed for this minimal residual disease setting after surgery. I believe at Guardant currently available is for patients with more advanced disease, if that's correct. So yeah, just having the complicated discussions but it's great to have all this data coming out. And what I thought was really interesting, particularly from the GALAXY study, was that it looks like chemotherapy can clear circulating tumor DNA. I think if I recall it was about two-thirds of patients had clearance.
So that really gives hope for these sorts of studies for these patients who otherwise have a very poor prognosis. It's like a certainty practically that it's going to come back because it actually is in their blood already. And then I also... kudos to Dr. Dasari and his team for the CIRCULATE trial because it seems like her to not treat with chemotherapy for stage III. But I think about 40% of allcomers with stage III disease could be cured with surgery alone and so what a benefit to be able to identify those patients and spare them from the toxicities.
Dr. Eng:
Thank you so much for your input. So the key clinical takeaways from this first case is that circulating tumor DNA defined minimal residual disease is very strong prognostic marker for recurrence. Recent data suggests that circulating tumor DNA defined minimal residual disease and MRD-guided management of stage II colon cancer is non-inferior to standard of care. Ongoing clinical studies, which we encourage you to enroll to, will help answer additional questions. COBRA which is specifically for stage 2A is evaluating the role of adjuvant chemotherapy in low risk MRD positive stage II colon carcinoma. And CIRCULATE-US is a deescalation potentially in MRD negative low risk stage III and escalation of adjuvant therapy in MRD positive colon carcinoma patients.
So this brings us to the end of this case, please see the other segments for further discussion about the latest data in colorectal cancer or visit ascopost.com.
