We're here to talk, dude, you know?

Yeah.

[laughs] All right.

So, um, here are my disclosures.

So I think there's a few questions that come up, and I'll just break it down to, to very real-world questions for us in the clinic.

The first, what's the mechanistic rationale for this ctDNA-based MRD monitoring? And, you know, when you think about circulating tumor DNA, it is pervasive now across all these different questions we have in the clinic from early detection now and interception, all the way up to molecular profiling and looking at acquired resistance.

But what I'm going to focus on is this group-- is this question around, um, where that patient has no measurable disease on imaging.

Yeah.

All

right, so here are my disclosures.

So I think there's a few questions that come up, and I'll just break it down to very real-world questions for us in the clinic.

The first, what's the mechanistic rationale for this ctDNA-based MRD monitoring? And You know, when you think about circulating tumor DNA, it is pervasive now across all these different questions we have in the clinic from early detection now and interception all the way up to molecular profiling and looking at acquired resistance.

But what I'm going to focus on is this question around where that patient has no measurable disease on imaging.

Can we use CT DNA to kind of augment our surveillance and understanding of where that patient sits in their disease continuum? And in fact, Depending on that patient's baseline risk of recurrence, the question is somewhat different.

So where a patient comes in with maybe a low risk of recurrence after surgery with curative intent, then the question is, can we de-escalate treatment, take it down a notch? And then for those patients who have an exceptionally high baseline risk after surgery with curative intent, is there an opportunity to be more intense, more to escalate our treatment to give that patient a better outcome? So we really need to be thinking about that baseline risk as we incorporate MRD testing into our practice.

I

We're here to talk to you, you know?

Yeah.

[laughs] All right.

So, um, here are my disclosures.

So I think there's a few questions that come up, and I'll just break it down to, to very real-world questions for us in the clinic.

The first, what's the mechanistic rationale for this ctDNA-based MRD monitoring? And, you know, when you think about circulating tumor DNA, it is pervasive now across all these different questions we have in the clinic from early detection now and interception, all the way up to molecular profiling and looking at acquired resistance.

But what I'm gonna focus on is this group-- is this question around, um, where that patient has no measurable disease on imaging, can we use ctDNA to kinda augment our surveillance and understanding of where that patient sits in their disease continuum? And in fact, depending on that patient's baseline risk of recurrence, the question is somewhat different.

Yeah.

But when you start someone on Folfax and let's say Nevo, do you do a pre-specified number or duration of doses of Folfax or do you treat to drops in platelets or neuropathy before you drop the oxaliplatin? And then what is your maintenance? Is it 5-FU Nevo? Is it Nevo? Is it individualized?

Yeah, so if you look at the data from our control arms of these randomized phase three studies and look at how the experimental arms are doing, what we're seeing are people are living longer and longer, right? So when the median OS is less than a year, things like neuropathy become less of a concern.

But if people are going to live two, even up to three years with metastatic disease, symptomatic peripheral neuropathy is a significant quality of life concern.

So for me, I'm looking at that patient's care continuum, not just what they're on in first line, but what their life is going to look like a year later.

When you consider that, I think that most of the benefit you get from oxaliplatin is in those first six to eight cycles.

So for me, I am rapidly tapering off the oxaliplatin after typically six to eight cycles to prevent that patient from having major quality of life implications from the oxali.

I usually will keep the 5-FU going because it rarely causes significant toxicity together with that biologic.

Do you factor in the liver mets? If someone has a bunch of liver mets, are you going to be less likely to give them single agent Pembro and maybe explain why you might think about it?

Yeah, I mean, it's a really great question.

And The data with PEMBRO suggests single agent activity where CPS is 10 or more.

So that's why that's attractive in this case.

There is substantial evidence that liver metastases and certain solid tumors do essentially create an immune tumor microenvironment that is more tolerogenic towards tumors.

So it's an interesting theoretical question.

It may be that I have not seen the paper, but I've not seen evidence that at least in gastroesophageal cancer, liver mets would predict for resistance to such a strategy.

Are you ready to call that person HER2 negative or are you going for a biopsy? And what about the converse? If the ctDNA is positive, do you need a biopsy?

Do you have any reservations about giving this Folfax-Zolbe-Nevo triplet in a PD-L1 negative patient?

Yeah, I would.

I think for a CPS0, I'm less inclined to give immunotherapy or immune checkpoint inhibitor therapy.

So this is a classic patient where it would be full FOX plus zolbatuximab in my clinic.

And In our case, at our institution, once again, it's a learning curve whenever you bring these new molecules into the clinic and into the treatment room, not just for us as doctors, but for our clinic staff.

Just to reiterate that point, slow infusion for that first cycle, right? The bad news is also the good news.

The bad news is that the nausea and vomiting can be extreme in some cases.

And also, because the Horizon trial used Kapox or 5-FU Platinum, would you give Folfax with Xani typically? We saw that in the phase 2, but not in the phase 3.

What are you doing in this first-line scenario, John? You also brought up sort of the importance of managing toxicity, so someone who's maybe a little bit more borderline.

Yeah, you know, this is the art of medicine, not the science, right? And we'll never have a trial where we can randomize 500 patients to either arm and answer this question.

I think the question for me is, what can this patient handle? What's the patient's goals? So an 80-year-old clearly is so deconditioned by her illness that she may be on the verge of being admitted.

So I think it's, first of all, just starting with a frank discussion about what that patient's goals are What are their sources of support? If we give an aggressive treatment, do we have support around from other family members, neighbors? So if the patient is wanting to be as aggressive as possible, What we've got here are some actual biomarkers.

When I see HER2 positive, I'm hoping it's IHC3+.

And, you know, assuming it's PD-L1 positive, I think the first question is, could this patient take, you know, is the heart function good enough to take trastuzumab, right? Or even a Zani, but I think, you know, assuming access is limited, it might be trastuzumab.

And then you would love to get in a situation where you could potentially give Pembro and add that in, right? And then the question is, what cytotoxic could you put on top? And I might start with a chemo-free and just kind of slowly layer in the cytotoxics.

But John, this case, we see these, like, how do you guys do it? Similar to...

But John, this case, we see these, like, how do you guys do it? Similar to...

Yeah, this is actually not an uncommon scenario.

We see this quite a bit.

And our general approach, number one, it is stage four disease.

It's systemic disease, but it's fairly limited in its extent.

But I would give this patient the best who's relatively fit, robust, and wants an active therapy.

I would give them the best available therapy.

John, you're going to continue and walk us through some Clawden data and talk a little bit about Clawden.

Again, the issue of chemo in this situation, do we really need the chemo? And a question from the audience, what about cell-free DNA to determine whether to use chemo?

So the atomic trial was the best trial design that we could think of in 2015 when it was designed, right? And Frank Sinekroop, who is the author of the study, is the first to admit that that's not the study he would have done today, if you could do it over.

But as you know, these trials take years and years to enroll and to accrue, and science kind of passes a trial design by.

There's a few things, basic principles of immunotherapy for MSI high colon cancer that we've learned since Atomic was designed.

Number one, MSI high disease is innately chemotherapy-resistant disease.

We've learned that from Foxtrot, where a neoadjuvant chemotherapy strategy was largely ineffective for those patients.

And then, of course, we've got Keynote 177, Checkmate 8HW, where immunotherapy is vastly superior to chemotherapy.

There are a lot of them.

What happened with him?

So this is an actual case from my clinic.

This is a 58-year-old who was referred for colonoscopy.

He saw the ad on television and submitted his sample, and it came back positive, so he got a colonoscopy.

They found what was initially thought to be an adenoma, went for extended right colectomy, had a classic low-risk T3N0 stage 2A colon cancer.

Moderately differentiated, no LVI, no perineural invasion, margins were clear.

No obstruction, no perforation, everything looked great.

But right now, what kind of penetration is there for Cologuard? Are you seeing a lot of patients like this who are picked up that way, or is it just sort of getting started? Yeah.