Suneel Kamath, MD: [00:00:00] So this this trial that the tech 24 trial was really looking at a pan G. I. Population evaluating tucatinib plus trastuzumab and then full fax chemotherapy across a number of different G. I. Cancer. The thing that was really the strength of it is that this is recognizing really that her to amplification is extremely important biomarker.
wE first found it in breast cancer, of course, and have been using gastric cancer and esophageal cancer for many years, but we’re starting to recognize more and more that this does really have kind of a tumor agnostic importance to it, where really, HER2 amplification can be seen in biliary tract cancers and other GI cancers, colorectal as well now as an approval.
And It just really speaks to the importance of looking for these rare mutations. It might only be a few percent of patients and each of these diseases, but they’re often very responsive [00:01:00] to HER2 directed therapy. And so this trial was really looking at a PAMGI, colorectal, biliary tract and then upper GI gastric and esophageal cancer.
And then in the, in that population for the gastric and esophageal cancer, because of the approval of immunotherapy that came as this trial was ongoing Pembrolizumab was also added to that particular arm. So it was FOLFOX, Pembrolizumab, trastuzumab, and Zucatinib.
OncologyTube: Fantastic. Okay. So can you explain the history behind using tucatinib in combination with trastuzumab and FOLFOX for patients with HER2 positive metastatic GI cancers?
And what were the primary goals of the SGN TUC 024 study.
Suneel Kamath, MD: Yeah, so I would say, the combination with tucatinib and with trastuzumab and fluoroprimidine really came about from breast cancer. Originally there, there’s approval there for capesidabine, the oral form, of course, the five of you with trastuzumab and with [00:02:00] tucatinib.
And Yeah. That sort of gave us, the backbone of using a full FOX type regimen in combination with with tucatinib and trastuzumab. And then from that, there’s now this approval for tucatinib and trastuzumab without chemotherapy in later lines of treatment, second, third, and beyond in colorectal cancer.
And so I think this trial was really trying to build upon that foundation of. What sort of a combination of chemo or chemo and immunotherapy with the two or two targeted agents? Can we, move the needle with improving response rates and then also, improving survival as well? When in doing so and also I think trying to learn and ensure that These combinations are safe, certainly as we build in terms of the number of agents used, there is a risk toxicity as well.
OncologyTube: All right you touched on my next question here, which is the study mentions manageable safety and preliminary anti tumor activity. Could you elaborate on the safety considerations and any [00:03:00] notable anti tumor responses observed in patients with HER2 positive MCRC and gastroesophageal
Suneel Kamath, MD: cancer?
Yeah, definitely. I’d say this combination overall is pretty, pretty well tolerated the the main feature certainly to, to keep in mind as with all, her two targeted therapies, many of them have some EGFR activity to them as well. So cabinet was designed specifically to mitigate that.
To some degree, to have more selectivity for her to and a little less activity for EGFR, but there certainly still is. And the consequence of that largely is diarrhea is common with this drug and also in combination with full Fox chemotherapy. So the vast majority of patients will have diarrhea of some grade.
Most are low grade. And the grade three, four rates, we’re really in the kind of 20 to 30 percent territory in the study. Others certainly to keep in mind are rash, skin [00:04:00] rash is also somewhat common. Nausea, loss of appetite as well. And then of course, the study, we did see a number of Cytopenias, which, of course, are all due to the chemotherapy largely.
Certainly, Neutropenia and Thrombocytopenia were observed, but I don’t think that the Zucatni really had much to do with those things. So certainly, important to keep in mind, we’re combining this with chemo, so all of the usual chemotherapy toxicities we have to watch for and treat along the way.
But yeah, as far as efficacy is concerned, I think the numbers here were relatively small. Of course, because it’s early in the studies journey, I would say but there definitely were, many partial responses that were seen in particular in gastroesophageal cancers.
I have to look at here real quick too. Yeah, the partial response rate was 40% that was seen in this study that was in, in 10 patients in the gastroesophageal cohort. And I think importantly too, the disease control rate was 100%. So no patients had a best response of progressive disease, which [00:05:00] this was, somewhat of a, a difficult to treat disease for sure.
And just to see, that level of disease control is really unheard of. If you think about with full fox and Pemberlizumab and a non HER2 selected population, that disease control rates probably, 60, 70%, so to be at a hundred is really quite impressive.
And some responses also were seen in colorectal cancer as well.
OncologyTube: All right, fantastic. The study mentions ongoing randomized phase 3 study, the Mountaineer 03, comparing this regimen with a standard of care for HER2 positive RAS wild type MCRC. What are the expectations or potential implications of the results?
from this upcoming phase three study in terms of treatment options for these patients.
Suneel Kamath, MD: Yeah, we’re definitely really excited to see, the Mountaineer O3 trial has been ongoing for quite some time now. And we’re hoping basically to find that, it’s interesting in colorectal cancer.
Right now we have an indication for trastuzumab and Ducatnib as a second or third line regimen, largely. But really, even though we’ve known [00:06:00] about her to, positive disease which is in about 3 to 5 percent of colorectal cancer patient. That’s significantly enriched in the left side especially.
So I would definitely call that out. Very important for oncologists, make sure that you’re testing everyone, but especially people with left sided tumors. Even though we’ve known about that rate, 3 to 5 percent of patients having this, we really have not had a first line approval for anything actually in colorectal cancer.
And so what we’re hoping to see in this study is that there’s some synergy between chemotherapy and HER2 targeted therapy up to cadmium and trastuzumab. Such that, we’ll see an improvement in response rate and then hopefully also with survival, I think as we see across so many different tumor types, it’s very important to get in as much therapy as possible up front, when patients are at their fittest, when the disease is newly diagnosed, it’s often at its most aggressive.
And so I think sometimes, hitting it hard earlier can give you more bang for your buck. And so we’re hoping to see that this study proves, that by moving her to targeted therapy in the frontline [00:07:00] setting, we can improve survival.
OncologyTube: Excellent. So last question, what are the key takeaways for our oncologists watching this online from the SGN TUC 024 study?
Suneel Kamath, MD: Yeah, I would say that the key takeaways for me from this trial really are, very encouraging activity, both in gastroesophageal cancer and in colorectal cancer as well. So really, gives me, hope for again, moving this regimen into the frontline setting for colorectal cancer.
And also, I’m hopeful to see, especially thinking about the gastroesophageal cancer space, I think we were all a little bit disappointed when the Kino 811 trial came out and the benefit of Pembrolizumab on top of trastuzumab is less impressive than we had initially hoped.
And we really only saw the benefit. If you were HER2 positive and had some PD L1 positivity as well, but if you were PD L1 negative and HER2 positive, there really wasn’t any benefit for adding PEMBRO. And so it creates sort of an unmet need now where, hopefully [00:08:00] Tucatinib can fill that space.
Indicated to us that, maybe Pembroke is not enough and we need to add something extra to target the HER2 in the process. But again, I think in CRC especially, I think we’re really hopeful, this gives me even more hope that the Mountaineer O3 study will be positive and we’ll have a frontline indication for this drug for our patients.
All right,
OncologyTube: Kamath, a medical doctor, a gastrointestinal medical oncologist at the Cleveland Clinic in Cleveland, Ohio. Dr. Kamath, thank you so much for joining us today. Of course,
Suneel Kamath, MD: yeah, thank you for having me.