OrigAMI-1: Dr. Kanwal Raghav (2025)

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 with us Dr Kanwal Raghav from MD Anderson, and he’s going to tell us about his poster that was presented at ASCO-GI 25 welcome. Dr Raghav,

Dr. Raghav 0:23
Thank you. Manju. So I’m very excited to present some of this data, and one of the reasons for presenting this data is the drug amivantamab is sort of like the new kid on the block with two large first line and second line colorectal cancer studies, which are currently ongoing, Origami-2 and Origami-3. These are global studies and are looking at the efficacy of this drug and its safety in first and second line, against standard of care. So hoping to accrue patients on it and seeing if we can move the field in the right direction. But this is Origami-1. This was the first study of amivantamab with or without chemotherapy in patients with colorectal cancer. There were multiple cohorts in this study, we are concentrating here on the right sided metastatic colorectal cancer.

Dr. Raghav 1:28
So anti EGFR antibodies, cetuximab and panitumumab are currently the mainstay of treatment for RAS BRAF, HER2 negative, wild type patients, which generally tend to be more efficacious in the left sided population than the right sided population. Although some data is showing up that with hyper selection, even within right sided population, there could be efficacy. There are, unfortunately many resistance mechanisms to anti EGFR therapies, MET being one of them, however, no MET inhibitors are routinely used in treatment of metastatic colorectal cancer, despite the fact that met expression is ubiquitous in colorectal cancer. It is associated with poor prognosis and can lead to resistance to anti EGFR therapies. Amivantamab is a bispecific EGFR-METantibody which also has immune cell directing activity and is currently approved in non small cell lung cancer. It has also shown promising activity in Ras, BRAF, wild type left sided colon cancer in in the Origami-1 study, the results of which were presented last year. Here, we are going to present the updated data for activity of amivantamab as a mono therapy and in combination with chemotherapy in right sided population, knowing that there is a differential effect of anti EGFR drugs in right and left sided population.

Dr. Raghav 3:11
So this was a global multi center study. The analysis here assess the efficacy and safety of amivantamab monotherapy in right sided patients who have had a second or third prior line. Prior anti EGFR therapy was allowed in these patients, and then in a second line setting after first prior line, it was used in combination with chemotherapy, and no prior anti EGFR was allowed for that cohort. So this is cohort C, cohort D and E, respectively. So you can see this is the overall design of the study. The study had left sided population -two cohorts, cohort A and B. We are going to concentrate on cohort C. And then cohort D and E allowed right and left sided disease, but we are going to specifically look at patients with right sided disease.

Dr. Raghav 4:10
So you can see there were 23 patients in cohort C, and about seven total patients in combination with chemotherapy in cohort D and E. This is a very standard makeup for a population of this type. You can see that about 43% of patients had had prior anti EGFR therapy in cohort C, and the primary tumor locations were spread across cecum, ascending colon, hepatic flexure and transverse colon. Many of these patients were heavily pre treated with up to three lines of therapy in the mono therapy cohort. So this is a safety analysis. No new safety signals were identified during the study over and above what we know about amivantamab. As you can imagine, the anti EGFR activity does lead to typical side effects like acneform rash, a majority of these were grade one and grade two, with only about 4% being grade three or higher. And then there are some side effects, such as hypoalbuminemia and peripheral edema that are associated with the MET inhibition. And you can see, again, majority of those were were grade one and two, with 13% being grade three or higher. And then there are some infusion related reactions that you can see and some alt AST elevation. But most of these side effects are still mostly grade one and grade two, and with few being grade three. So this is the efficacy endpoints. You can see that in this highly treatment refractory population, about 43% of those which had already had an anti EGFR exposure, the objective response rate was 22% with a single agent, and about 43% in a second line setting, in combination with both FOLFOX and full FOLFIRI. The key here is that the duration of responses were long about 9.8 months in the monotherapy cohort, and it was not evaluable in the combination cohort, with range being from 5.8 months onward. There was also about 80% disease control rate, and the median PFS was about 3.7 and 7.4 months respectively. This is a waterfall plot, and you can see that there was one CR, about four partial responses in patients that were right sided, and then again, in the chemotherapy cohort, there were three partial responses. The lower table also shows some of the molecular makeup of these tumors. And as you can see, this occurred across patients who had TP 53 ,APC mutations, so there was evidence of activity across a wide range of mutations, including some of those that confer resistance to anti EGFR, such as PIK3CA, as you can see, this patient with the confirmed response actually did have PIK3CA mutation. This is a spider plot showing duration of responses. You can see when once those responses occur, many of those responses are long lasting. I think this is a key for this, where the median follow up was about 8.1 months for the mono therapy cohort and about 8.2 months for the combination cohort. And then, in conclusion, we do feel that amivantamab as monotherapy or in combination with chemotherapy, provided promising anti tumor activity with objective response of about 22% in mono therapy cohort and about 43% in the combination cohort. The safety profile was was very acceptable, with no new safety signals, it showed activity in right sided tumors across a variety of mutations, and then the Origami-2 and origami 3 are currently ongoing. So I think, this was, this was a key study. And I’d like to, of course, thank the patients and their caregivers and the study staff that made this study successful, we are hoping to see this activity and possibly the next analysis for Origami-2 and Origami-3

Manju George 8:53
Okay, thank you very much. Dr, Raghav, so you mentioned that for the left sided ones, results were available last year, right? Is there a lot of difference with between the left sided tumors and the right sided tumors in terms of the response?

Dr. Raghav 9:13
Yeah. So when you look at anti EGFR therapy, per se Manju, there is a definite difference between left sided & right sided tumors. Even prognostically, right sided tumors tend to do worse than left sided tumors. But if you look at the analysis of 80405 or some of the other studies, it’s quite clear that there are mechanisms beyond just the classic mechanisms like KRAS, NRAS, BRAF and HER2 and right sided patients do worse than left sided patients with anti EGFR therapy, even when adjusted for these factors.

Manju George 9:58
And the Origami-2 and -3 are enrolling right now, right? Do you have information about where all those these trials are open. Are they open at MD Anderson too?

Dr. Raghav 10:12
So they are open at MD Anderson, but they’re also open across multiple sites in the US and and these are two randomized trials. So the Origami-2 study is a 1L study that’s only for left sided patients who are RAS/BRAF wide type, and the randomization is to amivantamab plus chemotherapy of choice from the provider, and anti EGFR plus chemotherapy of choice of FOLFOX or FOLFIRI. And Origami-3 is a 2L study. So these are patients who have already received Bevacizumab plus chemotherapy in a first line setting, and then these patients subsequently would be getting amivantamab plus chemo versus Cetuximab or Bevacizumab plus chemo, but and the second line study allows both right as well as left sided patients.

Manju George 11:13
Okay, okay, so basically, what you’re saying is that for the first line trial, those would be patients, if they get on the experimental arm, they would not receive Cetux, because, I’m just asking it this way, because people are more worried about getting CETUX because of the skin reactions, right, so a lot of people like to get Bev first line, and then..

Dr. Raghav 11:38
That’s right, it is true that that side effect profile is concerning, but Manju is also very clear from the data that left sided patients do derive survival benefit when they are exposed to anti EGFR over Bevacizumab in first line setting. So I think the trial has been designed with the current standard of care in mind. But there is a possibility that patients who do not want to have anti EGFR in first line setting, for them, Origami-3 is an option, which would be anti EGFR versus amivantamab in a second line setting.

Manju George 12:22
Yeah. So that’s what I was trying to ask, really, is that if people did not mind getting anti-EGFR in first line being on this trial, there is like a 50, 50% chance to be randomized to the arm to get cetux. But if they really didn’t want it, because I think if they get on amivantamab, then probably it will be fine for them, right? Because it’s not the same as Cetux, right?though, the rash is kind of similar, maybe?

Dr. Raghav 12:52
Yes, yeah. So if you’re taking patient preference into view, then those that cannot get on Origami-2 can definitely get on Origami-3.

Manju George 13:04
Yes, yeah, that’s where I was going. Okay, so that’s really helpful. And then do you have any idea of the number of slots?Because so for I was under the impression that they have not started enrolling. So that’s not true. They have, actually both two and three have started enrolling.

Dr. Raghav 13:22
So we are activated here at MD Anderson, and we do have, like, I mean, there’s no specific slots for any particular site, but 1000 patient study, sorry, Origami two is 1000 patient study, and Origami-3 is about 700 patient study.

Manju George 13:41
Okay, okay. So it’s just that, like when they know that they’re all wild type, this would be a first line trial, to consider.

Dr. Raghav 13:49
Before you begin any treatment, and I think with the recent data, with BREAKWATER, add to it, the data from Keynote and Checkmate, I think we’ve created enough evidence to suggest that no patient with metastatic disease should begin any chemotherapy, prior to getting their molecular profiling, right? So I think everyone should focus as soon as they’re diagnosed, they should focus on, like figuring out their molecular subtype, because then they can either be a part of clinical trials with more targeted therapies, or definitely, if they’re BRAF or MSI, they can go to current first line standard of care, which would be IO and BRAF therapy,

Manju George 13:49
Yeah. Okay, that’s a great point, because I think that right now, for even, there’s a MOUNTANEER for HER-2, and then, like, there’s a G12C trial too. right?, ?

Dr. Raghav 14:50
they’re all coming towards the first line, right? Yes, and it’s quite clear from the current data that as you bring these drugs up in the first line you are increasing the relative benefit of these drugs.

Manju George 15:03
Okay, okay, that’s important to know. And then as far as side effects. So I think that this data would be most useful when people are considering the second line the Origami-2 and 3. And they might be concerned about the side effect profile. So basically, what I heard you say is that most of them were grade one, maybe some, there were some grade two and grade three, right?

Dr. Raghav 15:27
No, most of them are grade one and grade two, okay, but very few of them as we can see it in the mono therapy cohort, at least here, about four to 5% were grade three. With regards to the rash, right. There are some side effects like hypoalbuminemia and peripheral edema that can also be more, but again these are manageable with dose reductions and those modifications and the rash can be very well controlled with proactive management and prevention of acneform rash,

Manju George 16:02
Okay, and the same thing like getting doxycycline? cs,

Dr. Raghav 16:07
Oral antibiotics, topical antibiotics, steroids, when needed, yeah

Manju George 16:15
Okay, okay, so the other question was, the mono therapy arm, so that is not relevant anymore, right? Because now the ones, the ongoing trials, the phase three trials are with combination with chemotherapy, right? So, I mean, I’m asking these questions because, if somebody wanted to know, if there’s a discussion, and they want to know, like, how does it compare with Cetux? Like, what would you say? Is it kind of half the side effects, like, yeah, ball park?

Dr. Raghav 16:52
Yeah. I don’t know. That’s where the trial comes into the picture. Manju, I think the motivation for anyone to participate on that trial should be because we feel that there could be higher efficacy, right? I don’t know about the safety signal as yet, how it would compare, but, yeah, I mean I think in the clinics, the rash is very much like an anti EGFR rash, but what would be the proportion, or what would be the percentage of patients getting that rash, or the severity? That remains to be seen.

Manju George 17:41
Okay, this is very helpful. I think that’s it. Do you have any thing else that you want to convey?

Dr. Raghav 17:50
No, just the emphasis on getting molecular profiling as soon as possible, and then trying to participate. I mean, these are big trials, and they need patient participations to, I would say, to answer the scientific question, in a relevant fashion, we do need patient participation. And there is enough data that there is a clinical equipoise, that there is good activity of these drugs, okay?

Manju George 18:22
And, and, because they are phase III, you get standard of care anyways, right?

Dr. Raghav 18:28
So we’ll definitely give standard of care. So there is no way you’re getting anything that’s less effective, even if you get on the control arm now.

Manju George 18:38
Okay, okay. Thank you so much. This was very helpful.

Dr. Raghav 18:42
All right thank you, Manju, appreciate it.

Manju George 18:45
Thank you. Take care. Bye.