Sakti Chakrabarti, MD: [00:00:00] So Dream GI is a national database through which we collect data on localized GI cancer patients who have MSI high tumors and who have received immunotherapy up front. We also call it new adjuvant immunotherapy. The idea behind this database is that new adjuvant immunotherapy is being given to patients who have localized GI cancers and MSI high tumor, right now, outside of a clinical trial, because many of these patients are not good surgical candidates.
If those patients are getting the treatment, it makes a lot of sense to collect that data and analyze that data in a couple of years. And that’ll give us invaluable information on safety and efficacy of immunotherapy for this group of patients. And more importantly, what I anticipate that it’ll tell us that a proportion of these patients can be [00:01:00] cured.
just with immunotherapy, without surgery, without radiation, without chemotherapy. That’s what I anticipate in the end, but we have to see. Now, there are a few other critical informations I want to share with you and with the audience to explain why immunotherapy makes a lot of sense for a proportion of localized GI cancer patients who have MSI high tumors.
Number one, Immunotherapy has remarkable anti tumor activity against MSI high tumors. Now this is a, this is not a new information. Pretty much everybody knows about it. But what is not very well known is this, that immunotherapy works better in early stage MSI high GI cancers. When the tumor burden is smaller, immunotherapy works much better.
For example, if you look at stage 4 MSI high colorectal cancer patients getting immunotherapy, their complete response rate is [00:02:00] like 11 to 13 percent. But then early stage patients, like MSI high stage 2 or stage 3 patients, when they get immunotherapy, like in NISH 2 study, even one month of immunotherapy led to a complete pathologic response close to 70 percent of patients.
So the difference is that traumatic when the tumor volume is not that high. Other important information, again, this is not very well known, which is immunotherapy works better before removal of the tumor. When the tumor is in situ or in the body. immunotherapy works a whole lot better.
And there is actually a preclinical paper highlighting this idea elegantly published in 2017 in Cancer Discovery. Lou is the LIU et al., is the group who published this data. So based on all this information, I think immunotherapy in localized GI cancer patients who have MSI high tumor [00:03:00] make a lot of sense.
And this is being done. I am doing it. Many of my GI oncology friends are doing it. So I thought it makes a good sense to collect all this data and analyze that data in a few years. It’ll give us a lot of information on safety and efficacy of immunotherapy for this group of patients. All right,
OncologyTube: excellent.
What are the key factors that influence the decision to administer neoadjuvant immunotherapy to patients with DMMR, MSI gastrointestinal cancers, and how did these factors vary among the different tumor types in the study?
Sakti Chakrabarti, MD: YeAh. Important question. Absolutely. So currently, for early stage MSI high GI cancers, surgery is the standard of care.
So that’s the current standard of care. Although, let’s say for early stage colorectal cancer, our current treatment fails in about half of these patients. In about 40 to 50 percent of these patients, [00:04:00] after they get curative treatment, which consists of some form of surgery and or chemotherapy, we’re you know, half of these patients will have cancer records.
So outcome is not great. But then so right now though we cannot offer immunotherapy to everybody because surgery is still the standard of care since you do not have long term data. But then right now, when a patient comes to me, they have to satisfy three criteria, before I offer immunotherapy to them.
So let’s say there is a stage two or stage three colon cancer patient came to me. and ask me, can I get immunotherapy because I do not want surgery? So they have to satisfy three criteria. One is they have to have MSI high tumor and that’s the easy test to do. Secondly, they have to have a poor surgical candidate, meaning, they have other risk factors.
Let’s say, emphysema or other heart problem, kidney problem for which they cannot get surgery or surgery will be [00:05:00] associated with high risk of morbidity. So that’s the second criteria. So they have to have a they have to have surgical risk, before we can offer immunotherapy.
And number three patients should not have any contraindication to immunotherapy. liKe organ transplant or having an autoimmune disease and such. So these are the three criteria I would consider before I offer immunotherapy to such patients.
OncologyTube: Can you elaborate on the safety profile of NIT and this patient population, particularly in the incidence and management of immunotherapy related adverse events and whether there were any notable differences between the types of immunotherapy be used?
Sakti Chakrabarti, MD: Yes. Most of these older patients we generally offer them single agent PD 1 blocker, which is Pembrolizumab most of the time, like in my dream GI initial studies, 80 percent patients received Pembrolizumab. Now Pembrolizumab has a very long safety data [00:06:00] and very high safety profile. So I would quote two separate sources.
One is, there was one paper presented or published in the European Journal of Cancer only a few days ago. The first author is Julie Brammer. So they analyzed about 9, 000 patients who received temporal monotherapy for various kinds of cancer. And they evaluated what’s their, what’s the risk associated with single agent Pembroke?
And here is the data. Discontinuation because of immune related adverse event, the discontinuation rate was only 3. 6%, and then only 0. 2 percent patients died because of immune related adverse event. And then serious toxicities like grade 3 to 5 immune mediated toxicities. occurred only in 6. 3 percent of patients.
So this is a huge 9000 patient database. So that’s one source. Second source, we have actually published a, [00:07:00] um, systematic review yesterday at ASCO GI on the safety of pembrolizumab. So what we did, we collected data on patients who have received who have received PEMRO, single agent PEMRO for various GI cancers.
It’s about 3, 000 patients, and we have seen similar safety profile. Discontinuation rate is low death because of immune related adverse event is less than 1%, and high grade toxicities are typically less than 10%. So I think we can say the safety profile of immunotherapy, we have been using immunotherapy for over six, seven years now.
So I think we’re pretty comfortable with the safety profile of immunotherapy at this point.
OncologyTube: All right, excellent. Given the promising initial findings of improved responses and progression free survival, what future research or clinical considerations do these results suggest for the use of neoadjuvant immunotherapy in DMMR, MSI, GI cancer patients, especially those [00:08:00] with localized or oligometastatic disease?
Sakti Chakrabarti, MD: Yeah, so what I anticipate that a significant proportion of these patients will be cured just with immunotherapy. No surgery, no radiation, no chemotherapy. That is my anticipation based on the data I have seen and based on the data I have published and based on my clinical experience with patients.
I have a significant number of patients who are getting immunotherapy as their sole treatment because they could not get surgery. But however, we have to answer a few questions. Number one, what is the duration of this immunotherapy? We do not know that for sure. In some studies, they have used immunotherapy for six months, in some studies for one year.
So it’s, and in one study like NISH 2 or NISH 1, they have used immunotherapy, the doublet immunotherapy, which is EP and NEVO, they used for one month. [00:09:00] So we do not know In a how much immunotherapy they would need a number two challenges, which I think we have to circumvent before we can bring immunotherapy in the forefront for this early stage patients is that we have to figure out a way how to monitor these patients in a how to confirm that this patient have actually achieved complete response.
And we can just continue to follow them without doing any surgery or anything else. Now, circulating tumor DNA is one of the promising tools we have. And I have published some data. I’m gathering more data in that area. So I think these are the critical questions we have to answer before we can bring immunotherapy to the front line for these early stage patients.
OncologyTube: All right, so this has been an interview with Dr. Sakthi Chakrabarti, medical doctor, GI oncologist for the University Hospitals in Cleveland, part of the Case Comprehensive Cancer Center. Dr. [00:10:00] Chakrabarti, thank you so much for joining us
Sakti Chakrabarti, MD: today. Thank you for this opportunity. Have a great day.