Manju George  0:00 
Hello everyone. Welcome to Doc Talks. I’m Dr Manju George, the Scientific Director at PALTOWN Development Foundation, the nonprofit that supports COLONTOWN. Today, we have Dr. Christine Parseghian with us, and she’s going to talk to us about her new trial. But before we get into this, I would like to ask Dr Parseghian how she got into GI oncology, and what are some of the areas that are of interest to her? And again, to remind you that a recording of this talk will be posted in COLONTOWN University. We will first cover a this trial, and then we will have a question and answer session. So welcome, Dr Parseghian.

Dr. Parseghian  0:39 
Thank you so much, and thank you for having me. It’s it’s a pleasure to be here. So a little bit about myself. I’m one of the associate professors of GI Medical Oncology at MD Anderson. My focus of interest is not only CRC, but particularly patients with colorectal cancer that are resistant to first and second line therapies, and so I have a strong interest in anti EGFR rechallenge, KRAS G 12 C therapy, and KRAS G 12 C rechallenge as well. So subpopulations of these patients that have the more unfortunately, the more aggressive biology, and trying to improve outcomes. In terms of how I got into this field, it’s fairly straightforward. When I was 13 years old, my mom was diagnosed with colon cancer. I was young, and she was very involved in my schooling, and so she did not want to get adjuvant chemotherapy, because she wanted to be there to support me. And of course, I did not know enough to try to persuade her. So she did not get adjuvant chemo. She then went on in and of course, when a few years later, because she did not get adjuvant, she was higher risk for recurrence, and indeed, she did, she had metastases to her liver. Luckily, she was in Boston under the care of Dana Farber and MGH physicians, and she was able to get a curative hepatectomy, and now two, almost three decades later, she is well. And at that point, when I was only 16 or 17 years old, I decided to make more of an influence and be someone to try to persuade someone like my mom to have gotten adjuvant chemo, and, more importantly, other therapies in the metastatic setting. So I promised her, and I promised myself at that point that I would go to medical school and I would focus on oncology, and particularly, CRC.

Manju George  2:58 
Yay. Wow. Thank you for sharing your personal inspiration of how you are in this field now, and I’m sure that you can really identify with a lot of patients that come to you, and to be able to provide them the care that they’re seeking. So thank you very much.

Dr. Parseghian 3:17 
I wanted to give a little bit of background on why we’re doing this trial. So as many of you probably know, KRAS G 12 C mutated CRC is relatively rare in colon cancer. About 2 to 4% of patients have this mutation. Unfortunately, of those that do, it is more of an aggressive phenotype. The biology is more aggressive, patients compared to G 12 C wild type patients, do kind of relatively more poorly and are nonresponsive to other therapies to the degree that other wild type patients are. So thankfully, we are constantly looking for directed therapies against K RAS. So there was a G 12 C inhibitor in fact, multiple now that has been developed. One is adagrasib and in combination with anti EGFR such as cetuximab, and another is sotorasib, another G12C inhibitor that has been combined with panitumumab. Both have shown very nice responses in a patient population that is very heavily pretreated, in these patients that were on, for example, third line therapy. otherwise their options are a clinical trial versus standard of care, as many of you know, lonsurf plus Avastin, fruquintinib now with the approval or Regorafenib. And as we know, the response rates to third line therapy range anywhere between 2 to 7%. So we knew we had to do better, and thankfully adagrasib and Cetuximab, for example, has done just that. So Kopetz and colleagues just presented the data from Krystal-1, which is basically a combination of different kind of patient populations that they looked at together who had KRAS G, 12 C mutation and received adagrasib and Cetuximab. They have found, kind of the most dramatic response, I think, of the combinations that have been kind of evaluated to date, the objective response rate that was found was 34% with a disease control rate of about 85%. I think that objective response rate, again, 34% is is tremendous, in combination with, in basically, in relation to other third line regimens. Further, not only was it effective, it was deemed to be quite safe and potentially even less toxic than known third line therapies. So based on this data, you can kind of go on to the next slide, based on this data, and then also prior data that has come out of here at MD Anderson with Dr Morris and colleagues, and also, Dr. Corcoran from MGH, we have found that in other highly mutated and aggressive tumors, such as the BRAF V600E population of CRC, that the combination of, for example, the Braf combination, in addition to PD 1 or immunotherapy, has shown a significant improvement of objective response. So, for example, we all know the Beacon trial by Kopetz and colleagues that was, that was presented at and published in NEJM in 2019. This is an exciting trial, because these BRAF patients have an extremely aggressive disease, and so we were very excited, even with a 20% objective response rate, but we knew we could do better. So just recently, at GI ASCO, Dr Morris and colleagues presented very exciting data showing that, in fact, when you add an immunotherapy or checkpoint inhibitor, in this case, it was nivolumab, the objective response rate went from 20% to 50% which is just tremendous. So we use that as a little bit of hypothesis building for our own trial. And we know based on preclinical models that, similarly to BRAF, what happens in this KRAS G12C population is that we’ve shown, this like preclinically in mouse models as well, that adagrasib when given, enhances and basically reconditions the tumor microenvironment to then basically improve susceptibility to immunotherapy. So the hope that adagrasib and cetuximab looks great. It’s much better than third line therapy in this population of patients that are potentially able to get this regimen, but we can certainly do better than 34%. So our protocol that was just activated is a multi center phase IB/II study. It will be at MGH in Boston and MD Anderson here in Houston. It is a combination of adagrasib which is the G 12 C inhibitor, in combination with Cetuximab, the anti EGFR, and then, in this case, the checkpoint inhibitor, or the immunotherapy drug is Cemiplimab. This study will be in patients with metastatic or advanced colorectal cancer, who have a KRAS, G12C, mutation.

Dr. Parseghian  9:14 
A little bit about what we’re looking for. We are looking primarily to ensure that this has an objective response rate. So a response rate we’re looking for, can we do better than the 34% that was seen in Krystal-1? And also looking obviously at safety and tolerability. There is a safety lead in with about six patients. So that’s the Phase 1b component. And then we will do a dose expansion with several more patients, with a maximum number of patients to be 31 divided essentially equally between MGH and MD Anderson. We’re very excited about this trial. I think it can certainly, hopefully help our patients, based on the preclinical data we have and based on the Braf story, which is just super exciting. And obviously this patient population is very biologically aggressive, and I think again, we can do better than 34% so looking forward to having patients come over. We are really trying to get patients with KRAS G, 12 C mutations in quickly, because of course, that biology is difficult to treat. So if we can get them on a clinical trial that’s very important. And and, you know, just to talk a little bit about inclusion, which I which I failed to mention, we are looking for patients, like I said, that have the KRAS G 12 C mutation, but have also had at least one line of prior therapy. So that would include at least 5FU. They will need to be microsatellite stable KRAS G12C mutated, like I said, but also would not have had received prior checkpoint inhibitor, like a PD 1 inhibitor, and not have received prior KRAS G, 12 C inhibition. So this is not a rechallenge study. It is an upfront treatment with KRAS inhibitor in combination with immunotherapy. Thanks so much.

Manju George  11:25 
Okay, thank you very much. So now that we have the slide here, maybe we can start with questions about this. So you’re saying that it can be they need to have been exposed to 5FU. But do they need to get a certain amount of cycles containing 5FU or?

Dr. Parseghian  11:45 
No, so the the inclusion would be, progression on 5FU based therapy, or intolerability to at least one line of therapy. So if you got FOLFOX or FOLFIRI and did not tolerate it, and your local oncologist  had to take you off, then you would still be considered for the trial

Manju George  12:09 
Okay. And then I also noticed that prior exposure to cetux or EGFR inhibitors is not an exclusion.

Dr. Parseghian  12:17 
Correct. That’s right. So two sites open at MGH and MD Anderson being the two sites. So it will be 19 patients, but potentially up to 31 based on if we see any toxicities, etc, dose expansion. So yes, we, you know, this patient population is, like I said, rare, but we’re seeing them come through our doors. And you know, we anticipate this, this will be kind of a highly sought after trial, because we really are trying to get these KRAS G, 12 C patients early so that we can improve the duration of response, not only response rate, but the beauty of immunotherapy is it helps us with duration of response, and it basically allows your body to help you extend the duration of your therapy. And so if we can do that, that would also be a significant benefit for patients.

Manju George  13:25 
Okay, what about early stage patients who have progressed on adjuvant chemo? Would they be eligible?

Dr. Parseghian  13:33 
So if they’ve progressed on adjuvant I guess that would mean that they are metastatic. Yeah. So any line of prior 5FU based therapy would count,

Manju George  13:47 
okay, okay. So that’s great,

Dr. Parseghian  13:49 
Even if it was in the adjunct setting,

Manju George  13:51 
okay, so, yeah, even in the adjuvant settings, so and again. Then the important thing is for patients to know if they are KRAS G12C, like upfront, so that you even when they’re starting first line therapy, this is something to keep in mind, because the moment they progress, they can get enrolled

Dr. Parseghian  14:08 
Exactly, exactly, very important to stress, and I know we’ve probably talked about this at length, stress to the local oncologist, please get KRAS testing, BRAF testing and MSI at the very least, as soon as you’re diagnosed with metastatic cancer.

Manju George  14:26 
Okay. And then this is also for rectal cancer, both colon and rectal,

Dr. Parseghian  14:30 
Correct

Manju George  14:31 
Yes, okay, And then there are no biopsies. It looks like you’re basically going to be looking at CtDNA like liquid biopsies. So no biopsies involved other than that,

Dr. Parseghian  14:41 
No, there are. So there isn’t a pre- treatment biopsy, a tissue biopsy. But then there is an on treatment biopsy, and we are requiring them so that we can look at the tissue change over time, in terms of what is happening in the body and at a tissue level that we can do deep sequencing on to look at resistance in this population. And that’s how we’re really going to learn from this patient population. You cannot do that, the extent of that deep sequencing, the RNA sequencing, etc, on liquid biopsy, unfortunately.

Manju George  15:25 
Okay, so then I would say that from a patient perspective, what is important is that they should have progressed on 5FU containing chemo. They should also have metastatic disease, which is amenable to being biopsied, if it’s a mandatory biopsy, that is part of it, right? So these are the two things for patients to remember, Okay, sounds good. And then what else? And the hope is that the ORR will improve from 34% to higher, following what you have seen with the strategy for BRAF, right? And you’re also saying that you would like to get patients by having this inclusion criteria, you would like to get patients relatively early in their treatment journey than somebody who’s much later and have gone through multiple lines. Okay, so I think those are three things that we could definitely talk about to patients when we are discussing this trial.

Dr. Parseghian  16:18 
If you’re G 12 C, and you’re not local you could get the 5FU based therapy at home, no problem. But understand, there’s sometimes a delay getting into places like MGH and MD Anderson. So upon finding out that you have a KRAS G12C mutation, I might already reach out, even before you start any chemotherapy, to MGH or MD Anderson, just to get the foot in the door to start the process.

Manju George  16:48 
Okay, okay, that sounds like great advice, yeah. And then, could you tell us a little bit about this, the immunotherapy, the Cemiplimab, it is a PD1 inhibitor, right?

Dr. Parseghian  17:01 
It is PD-1. It has been studied in other tumor types already, such as bladder cancer, is very well tolerated with very minimal toxicities, similar toxicities to other immunotherapies, such as colitis, diarrhea in patients, pneumonitis, an inflammation of the organs, essentially. But we don’t suspect that, based on other data that we’ve had from Cemiplimab in combination with other chemotherapies, we don’t suspect that it is going to kind of worsen the safety profile in a significant degree should be very well tolerated in combination. In fact, we’re giving the the full dose of Cemiplimab, which has been approved.

Manju George  17:49 
Okay, okay. And then can you also tell us a little bit about the the drugs, like so adagrasib looks like it’s an oral medication, and it’s twice daily every day, or is there a cycle like ?

Dr. Parseghian  18:01 
No, its twice daily, every day, so that you could take at home in the morning and in the evening. And the Cetuximab is IV, and that you do come to the infusion center every two weeks for the 500 mg per meter square is the standard dose, and the Cemplimab is also IV. That’s a little bit of a different timeline. So the Cemiplimab is every three weeks IV, and the Cetuximab is every two weeks IV. So there is a two week period where you’re here more often, you’re my friend, more often, that is the way that it needs to be dosed for safety.

Manju George  18:39 

Okay, okay, okay, that makes sense. I’m thinking, if there is any other question that I have, yeah. So the other thing is that, like I have seen, I don’t know how common it is in the US, but I have seen some, tumor testing reports which say,  something like G12X where they don’t know if they’re G 12 C. So could those patients apply for the trial? Or they should they need, like, a already known G12C status? Or is there any way to get the testing done with you guys as part of the trial?

Dr. Parseghian  19:13 
Yeah, you know, unfortunately, there are several G 12 mutations. So there’s commonly, more commonly, G12D mutations, for example. We are happy to run the test if you come to us, we can easily do that with the liquid biopsy. So just the CtDNA test to look at the molecular profile. We do not need to do biopsy for that. That will turn around in a matter of seven to 10 days. We will know the profile of the patient, and we can potentially get going on therapy.

Manju George  19:46 
Okay, okay. Thank you very much. And then the other question that I have is when we come to know that there are G 12 C patients, would it be possible for us to give them your contact information, or, who would be the contact person say, for example, at MGH, that we could tell them, hey, email these people, and then you can get on it right away.

Dr. Parseghian  20:08 
So if they could email me directly. And so my email address is [email protected], and I believe the contact at MGH will be Aparna Parikh. I don’t know her email address offhand, but she would be the contact or the lead PI essentially at MGH.

Manju George  20:33 
Okay, okay, that’s great. I think we will be able to provide Dr Parikh’s email address as a contact information () and then, so I was wondering if you could say a little bit about, you know, the Stand Up to Cancer part of the whole project, and how it’s a collaborative effort, and what’s going on in the background?

Dr. Parseghian  20:55 
Yeah, so they have been tremendously supportive, obviously, of this study and and all of the preclinical work that has led up to it and continues to be ongoing. The study would not have been possible without their financial, the grant support, and also the guidance, scientific guidance, that they have provided us along the way as well. So tremendously grateful. Really hope to make a difference in this patient population, and they were very excited and supportive of this. So we’re very appreciative of the funding and the support that they have given us for now several years.

Manju George  21:37 
Okay, okay, I want to disclose here that I’m a patient advocate on this Stand Up to Cancer catalyst project. And for me, what has been exciting is the collaboration between Dr Corcoran’s lab at MGH and the MD Anderson group. So it’s like the top brains on looking at resistance combining together their expertise, and then having all, everyone in this field, interacting and collaborating. For me, that has been the most exciting part of this work.

Dr. Parseghian  22:12 
Thank you.

Manju George  22:13

Is there anything else that you want patients to know about?

Dr. Parseghian  22:18 
No, I don’t think so. I think just really trying to get patients the care that they need. And again, please reach out to me directly. If you’re having a hard time getting in. I’m happy to see you.

Manju George  22:32 
Okay, okay. Thank you very much. What I’ll do is that once the video is posted, if people have questions, then I’ll bring them back to you. Before we end, I would like to ask you this one question. Do you have any advice for early stage patients who come to know about their KRAS status, about the impact of it on adjuvant therapy?

Dr. Parseghian  22:51 
Yeah, unfortunately, we have no data for adjuvant I would say they fall into the same category of patients that would be subcategorized by specific stage, whether or not adjuvant chemotherapy would be recommended, just based on what we know so far per guidelines. However, I guess I would say,  understanding that you are a KRAS G 12 C mutated patient, you unfortunately have a little bit of a different disease biology, which is a little bit more aggressive. And so if the local oncologist is recommending chemotherapy, I would highly encourage you to follow those instructions and go through with the adjuvant chemotherapy to at least reduce the chances of this coming back.

Manju George  23:41 
Okay, okay, thank you. And when you were explaining about your personal exposure to the disease and how you got into this, I was a little bit anxious about when you said that your mom’s cancer had come back, but I was very happy to hear that she got timely help, and then, when it became metastatic, she has been NED for a couple of decades, and I think that is also a story that is hopeful for patients. And so I really appreciate you sharing that, and I think that’s it. And thank you very much for joining us and providing all the information about this trial.

Manju George  23:42 
Thank you so much for having me.