ASCO 2022 Colon Cancer In-Depth Slides: MOASC Spotlight
May Cho, MD from UCI Health ASCO (American Society of Clinical Oncology) Annual Meeting Presentation
I have to start with this neoadjuvant and definitive immunotherapy in MSI high (locally advanced) rectal cancer (gastrointestinal cancers) (colorectal cancer), especially in localized disease with the New York time Arteris of full messages, exponential like a hundred times. And then, I will go over the role of CMMRD in the management of early-stage colon cancer (colorectal cancer, rectal cancer).
And finally, I will conclude the outcomes with optimized first-line therapy in metastatic colorectal cancer in 2022.
So first, I will start with neoadjuvant immunotherapy in MSI high (locally advanced) rectal cancer (gastrointestinal cancers) (colorectal cancer) is an early-stage disease. So for rectal cancer, our treatment regimens have evolved over the last 5 years. We are starting to use total Neo therapy, where we give chemotherapy.
Chemoradiation before the surgery was seeing that by putting all these chemotherapy (standard) chemoradiation before the surgery, we were able to get the clinical complete response and about 40% of the patients were able to get the non-operative approach an organ sparing approach, as that rectal cancer (gastrointestinal cancer) (colorectal cancer) postoperative comorbidity can be pretty tough on some of the patients with ilia syndrome, with the frequency of the bowel.
This has been what we have been adopting. And when we specifically look at the chemotherapy response, in particular, in deficient mismatch repair cancer, you can see that this is a FOLFOX study (This was presented ASCO (American Society of Clinical Oncology) annual meeting in cancer research). We gave neoadjuvant chemotherapy, and you can see that for MSI-H (MSI High tumor) tumors, it was 75% of the patient did not respond at the same time.
This European study (cancer research) showed neoadjuvant immunotherapy in colon cancer (colorectal cancer) (gastrointestinal cancer) has a very high response. We have our group and UC Davis Group have published the case series (about clinical trials to see about clinical complete response) showing that given immunotherapy as a neoadjuvant gave patients clinical complete response. Without radiation, chemo, and surgery, we were able to do that organ sparing.
One of my patients is 4 years out with the immunotherapy for one year. And then he’s been in clinical complete response. With this data, I wanted to present the late-breaking abstracts from the MSK Group, which is PD-1 blockade in curative intent therapy in an MSI high locally advanced rectal cancer.
So in this study (This was presented ASCO American Society of Clinical Oncology, annual meeting in cancer research in locally advanced rectal cancer), dostarlimab, which is the PD-1 blockade we’re given every 3 weeks for 6 months, they do an MRI and endoscopic evaluation. And the thought was that on those evaluations, if we can get the clinical complete response, they will be followed none operatively.
If they were to have residual disease, then we’ll go do the standard chemoradiation, and then we’ll follow the standard management. You were, we, the target response rate was 25%. So these are the patient’s characteristics, but I wanted to highlight that this is a small subset (in locally advanced rectal cancer).
Were There Any Serious Adverse Events?
So, it’s about 18 patients, and all of them have BRAF V600E wild type. And this is the data that was presented is a hundred percent of the patients. Had a clinical complete response medium follow-up stayed quite short for 8 months? So this is very impressive data a 100% clinical complete response (duration) in the first 14 patients, no grade 3 or 4 serious adverse events.
These patients never require chemoradiation or surgery. Of course, a longer follow-up is required. So this is my take home for this data upfront, and then definitive immunotherapy would become the center of K in MSI high DMMR. (locally advanced) Rectal cancer (gastrointestinal cancer) (colorectal cancer) is very hard to get 14 of 14 complete, and we know that FOLFOX doesn’t work in this subset of patients.
And it’s also correlated with the metastatic data. Some of the caveats are, of course, that the follow-up is to stay short. So in the longer-term follow-up, we want to see if that response (duration) is sustained.
ECOG-ACRIN study
The second question remained to be answered. What is the best IO therapy? Is single agent PD-1 alone sufficient, or should we use combination therapy? ACR has an ECOG-ACRIN study (ASCO annual meeting (American Society of Clinical Oncology)). We were enrolling in this phase 2 study (cancer research) on IPI Nivo for 3 men with localized MSI high rectal cancer.
If you have any patients, please refer to us. My second topic is the role of ct-DNA MRD in the management of early-stage colon cancer (colorectal cancer). The problem of adjuvant therapy, especially in stage 2 cancer, is that we have to treat so many patients to save very few patients from recurrence, 80% of the patient would’ve been cured by the surgery, and then some may have a recurrence despite the chemotherapy.
So the question is, can we identify this subgroup of patients who has a high recurrence? And so then we can just specifically give chemotherapy to those. This is where the ct-DNA March is a molecular residual disease after surgery to identify these high-risk subgroups. So currently we have 2 main types.
One is tumor agnostic disease-specific. So what they do is they did NGS PCR of a common mutation in colorectal cancer review from Guardant. We do mutation in methylation and then methylation marker from the quest. The pro is it’s easy. It’s just the blood draw. And then you get the result (outcomes) in 10 days, or so the con is, of course, this is lower sensitivity.
And the next type is the tumor-informed disease agnostic. So what I mean is the patient tumor is sequenced, and then the test itself is specific for that patient. So the patient’s plasma is followed. Based on the mutation that the patient has. So the pro is very highly sensitive, but logistically, we have to get the tissue, and that shoe has to be sequenced, which can take like 4 to 5 weeks.
So we have no that, this is stage 2 patients, ct-DNA a positive and ct-DNA. None of the patients were treated. So you can see that if the patients have ct-DNA positive, they are 18 times more likely to have a recurrence than the ct-DNA negative. So we know that this test. Has a high prognosis factor.
So what we don’t know is whether we can really use this to help make the decision in an adjuvant setting. So that was trying to address in this randomized dynamics trial. So, stage 2 patients will enroll. There is a 2-group ct-DNA guided group and standard management in the ct-DNA guided group. If the ct-DNA a was positive, the patient was given adjuvant chemo.
If the ct-DNA is negative, they were observed in the standard management. The physician (of clinical oncology) can decide on the adjuvant physician based on the path. And then, the endpoint is a recurrent free survivor at the 2-year mark. This is a non-inferiority trial. So this is a tumor-informed, personalized test.
So each patient was sequenced, and then their plasma will follow for their own mutations. So these are the baseline characteristics very similar. So in terms of adjuvant treatment delivery, you can see that if the patient in the ct-DNA guided group got chemotherapy, only 15% compared to 28%.
However, when you have a ct-DNA positive, their risk is very high, and the patients were more likely to get the stronger doublet chemotherapy outside planning, doublet therapy compared to standard management. They tend to have more senior agents therapy which is a standard treatment. So this is a primary endpoint. The recurrence-free survivor is very similar. The non-inferiority is confirmed despite the ct-DNA being a guided group. The fewer patients got the chemo. If you look at the ct-DNA guided management group, and if you have ct-DNA negative, they never get any chemo.
They do very well. They did very well. And then, in the ct-DNA positive group, if they got treated, they do better than the one that they never got treated. So that kind of test. The ct-DNA also has a predictive factor. Once you have ct-DNA positive, it is not the point of no return.
If they have adjuvant therapy, you can help prevent the recurrence down the line. So if we subgroup the ct-DNA negative and low risk, these people do very well. 97, 90%, but ct-DNA made negative, and if they see a high-risk feature like LVI and PNI, the hazard ratio is 3 compared to all negative 1.
The same with T4. Its hazard ratio is 2.60, and then this is the hazard ratio for ct-DNA, a positive treatment.
So the one, so this is, that was mostly, those are all stage two. And then this study (cancer research) in Japan, data is high-risk stage 2 and stage 3. So what do we have data in terms of ct-DNA in high-risk stages 2 and 3? So I just want you to focus on ct-DNA, a negative group. So these patients are either T4 or stage 3 diseases.
They all have ct-DNA negative after surgery. They have 2 groups. The first group was given the adjuvant therapy, then all were observed, and you can see that these patients got the doublet plus chemotherapy. This data, even if you have a high-risk stage 2 or 3.
CIRCULATE Japan
Regardless of whether you got that adjuvant therapy or not, their disease-free survivor is very similar. So what do we conclude from this to try it? What do we know so far? We know that this system of the ct-DNA after the surgical recession has the strongest pro factor that is more important than TNN staging. and we know that adjuvant therapy can decrease the likelihood of recurrence, even in ct-DNA-positive cases. We are unsure whether we can really de-escalate the intensity or duration of adjuvant therapy in ct-DNA, negative folks, the dynamic, and CIRCULATE Japan data. Is it definitive for this T4 or high-risk feature? So personally, because of the hazard ratio between 3 and 2, I would say that gave the adjuvant therapy for the high-risk or T4 group. And then we have more data. The second question is for those who are ct-DNA, positive group, should we intensify it? And then, would that be a benefit now that we can really use the ct-DNA to guide?
CIRCULATE US Trial
Can we use the molecular targeted therapy in these patients? We were trying to answer in some of the randomized trials (clinical trials), but this is the adjuvant study (cancer research). It will take 5 to 10 years. So US has the CIRCULATE US trial that’s running for stage 3. Dr. Diani also has IIT and was given more chemotherapy.
Suppose the ct-DNA is positive after the adjuvant therapy. So if you have any patients, please refer to us for the study. Lastly, I wanted to end with optimizing first-line therapy in metastatic colorectal cancer in 2022. This is really an art. It treats metastatic colorectal cancer.
It really depends on like patient’s characteristic tumor characteristic. How much tumor burden do their patients have molecular characteristics? And then, of course, patients’ preferences. So who is the perfect candidate for the first line EGFR? They have to have a RAS wild type, no, BRAF V600E mutation.
SWOG 8045 study
We now know that high 2 amplifications are also resistant to EGFR therapy. We also know that right-sided tumors are also resistant to EGFR therapy. So this is from SWOG 8045 study. They retrospectively reviewed the data, and what’s shown is that if you gave Rituximab on left-sided, tumor median overall survival is almost 40 months compared to the right-sided tumor.
PARADIGM Study
So this PARADIGM study is trying to address it in perspective. This is RAS wild-type metastatic colorectal cancer, panitumumab plus FOLFOX or BEV plus FOLFOX over survivor is left-sided over survivor in a left-sided population. And you can see that there’s a statistically significant over survivor in the left-sided group who were treated with EGFR and FOLFOX progression-free survival was similar.
And we have known this for a way that anti-EGFR gave a better response rate than bevacizumab. So, for now, I always draw these diagrams for the fellow. So if you have metastatic colorectal cancer, you decide if MSI high or not. If it is MSS left-sided, RAS wild type, doublet plus EGFR is the optimal management.
So what do we do with these mutate patients and right-sided they have Warberg? Should we intensify it to the FOLFOX series? So this was addressed by the CAIRO study. So they are initially unreceptive colorectal livers bound a lot to find them mutations, and given FOLFOX series plus BEV or FOLFOX series plus BEV. And you can see the progression-free survival.
Statistically significant by giving the triple plus BEV compared to the doublet. And then there is 0 recession was also improved in triplet therapy. So for optimizing hand-picked patients, this RAS BRAF HER2 mutated and right-sided folks, the FOLFOX series, and BEV is optimal therapy. With that, I wanted to conclude (the outcomes) the summary.
So for neoadjuvant for the locally advanced high rectal cancer, immunotherapy should be a new standard of (cancer) care, and that alone can take (cancer) care of the patients to have a complete response. In terms of roles of ct-DNA is evolving for now. We have to treat the ct-DNA as a positive patient. Regardless of any TNN stage, ct-DNA, negative and low-risk folks, can be observed.
CAIRO5 Study
We’re trying to tease it out in this ct-DNA, a negative high risk of T4 patients for first-line (treatment) therapy. We have PARADIGM show the anti-EGFR should be used on the left-sided. The left-sided is all wild-type patients, and CAIRO 5 showed that the FOLFOX series in RAS BRAF mutated and the right-sided group.
We don’t have tons of targeted therapy like lung cancer, but we are slowly moving toward some of their targeted therapy in GI cancer. In particular, in colorectal cancer (for cancer care), we have HER2 BRAF V600E mutation. We have KRAS g12C trials (clinical trials) at UC Irvine currently run in Rituximab with the KRAS G12C inhibitor.
So if you have patients, please refer to us for immunotherapy for MSI high stable TMB. This is a very small population, but I just found 1 red fusion patient and will be enrolling the patients with lung cancer. With that, I wanted to conclude my talk. And if you have any questions, feel free to ask them.
May Cho, MD – ASCO 2022 Colon Cancer (colorectal cancer) Overview: MOASC Spotlight
https://oncologytube.com/v/41284
May cho, MD – Question and Answer MOASC Presentation
https://oncologytube.com/v/41306
May Cho, MD (Clinical Oncology) – About The Author, Credentials, and Affiliations
Medical oncologist at UCI Health specializing in the diagnosis and treatment of gastrointestinal cancers (gastrointestinal oncology) (colorectal cancer), Dr. May T. Cho, holds board certification in her clinical oncology field and has extensive experience in the field. She has spent a considerable amount of time working with UCI Health.