Evolving role of HER2/ERBB2 targeting in CRC: 2026 Updates: Dr. Raghav (2026)

[00:00:00] Manju George: Hello, everyone. Welcome to Doc Talks. I’m Dr. Manju George, the scientific director at Palatown Development Foundation, the nonprofit that supports COLONTOWN. I am really excited to welcome Dr. Kanwal Raghav, who is a professor of GI medical oncology, and associate vice president, ambulatory medical operations at the University of Texas MD Anderson Medical Center.

Dr. Raghav, welcome. I think we had a Doc Talk many years ago. I think when we actually started the Doc Talk series, we had you talk about ADCs, so it’s a pleasure to have you come back again and talk about the evolving role of HER2 targeting in colorectal cancer. So welcome.

[00:00:46] Dr. Raghav: Thank you, Manju.

It’s very interesting that we talk. We started talking about ADCs, and there will be a flavor of this in this coming talk. Today I’m gonna talk about something that’s really close to my heart. It’s one of my passions when it comes to research, which is the evolving role of HER2 targeting in colorectal cancer.

When it comes to colorectal cancer, HER2 has been a fairly new development. In breast cancer, HER2 has been known and targeted for a very long period of time. But more recently, there have been multiple therapeutic developments in not just colorectal cancer, but also lung cancer, gastric cancer, bladder, GYN, and GU cancers.

So this is a very powerful precision medicine and target-driven approach. And I think that in colorectal cancer, it holds tremendous promise. So I’m gonna start with this case. A picture is always worth a thousand words, and when you start looking at some of those year numbers on there you notice straight away that this is someone who was diagnosed with metastatic disease back in 2013, and then you notice another number there, which is 2020.

And this is a seven-year duration from getting from one type of therapy to another type of therapy, which is unheard of in colorectal cancer, barring exception of MSI-high CRC treated with immunotherapy. This is an example of a patient who was diagnosed with de novo synchronous metastatic disease with lung involvement, lung lymph node involvement.

The patient was extremely motivated and participated on not one, but two of our clinical trials and other clinical trials going forward, was actually progressing on standard of care treatment prior to 2013. Was diagnosed a year ago, had received first-line chemotherapy with the then standard of care, which is FOLFOX and bevacizumab followed by cetuximab and irinotecan.

The first chemotherapy or first-line therapy with Bev and FOLFOX lasted for around six months sorry, about seven months or so. The next treatment with cetuximab, which is an anti-EGFR antibody and FOLFIRI, so 5FU and irinotecan, lasted for a very short duration, only about three months with progression on the first scans.

The patient then enrolled on one of the earliest clinical trials for dual HER2 inhibition– a strategy wherein you target HER2 not with one but two drugs and almost had a complete response radiographically. Patient was actually off the treatment for a relatively long duration of time, and as you can see did not require any subsequent therapy for nearly seven years because of control.

And that duration of control is not only suggestive of how much the disease was being controlled, but how well the patient was tolerating the treatment. And then in 2020, patient ultimately had progression of disease. We retested for HER2 and was able to get onto a second clinical trial for HER2-targeted therapy this time in form of antibody drug conjugates, which, as everyone knows, are these antibodies on which we load a cytotoxic chemotherapy.

So it’s a very targeted chemotherapy which allows us to, with precision, deliver a higher dose of cytotoxic agents to tumors, restricting the side effects but amplifying their clinical benefit. And was on this treatment for nearly three years. Post that, patient progressed and was actually participating on a Phase I protocol with, again, a HER2-directed therapy, which highlights how we can sequence these strategies against the same target and still give our patients a meaningful clinical benefit.

So I wanna move from this case with the key lessons that at the time that this patient had HER2 testing done, it wasn’t considered standard of care. At the time this testing was done, patient didn’t have any other standard of care HER2 therapy options. But because of participation in clinical trials not only contributed to the larger evidence that now supports these therapies as standard of care for multiple other patients, which is an immense contribution in itself, but was able to have a significantly long disease course with controlled disease and responsive disease as would not have been possible with standard chemotherapy options.

So why does HER2 matter in colorectal cancer? This is the big question. This is a very big f figure, but I’ll try to break this down for our group. Colorectal cancer is not one disease entity. It is now subdivided into multiple smaller disease entities, and we are cutting out each of these pies and trying to target them appropriately rather than giving chemotherapy to everyone.

There are some names here that people are very familiar with, for example deficient mismatch repair or MSI-H. This is a group of patients that have a defect in their mismatch repair proteins so they accumulate a lot of mutations. This is the group that responds to immunotherapy in colorectal cancer with extremely good results and now does have first-line chemotherapy.

First-line immunotherapy is the standard of care, whether it is pembrolizumab as a single agent or nivolumab, ipilimumab as a combination. Then there is the BRAF mutant colorectal cancer. So this is a mutation that occurs in the BRAF gene. The reason why this subset is quite unique is because patients with BRAF mutant colorectal cancer have a very aggressive disease biology.

These patients rapidly progress, have poorly differentiated tumors and and many times they do not respond for a long period of time to conventional cytotoxic chemotherapy. This subset has also gained a lot of importance in the recent times because of two large studies, one in second line, one in first line, which is BEACON and BREAKWATER studies, that established combination of BRAF inhibition with chemotherapy as the first-line treatment option and now is the standard of care. In a population that otherwise didn’t respond to chemotherapy, the outcomes have improved significantly.

There are some really rare subsets like NTRK fusions. These fusions are found in less than 1% of patients, but they respond very well to NTRK inhibitors. And then you have what is always known about colorectal cancer, which is that it’s either RAS wild type or RAS mutant.

Within that RAS mutation status now there are newer targeted therapies for a smaller subset of these RAS mutations called KRAS G12C, which happens in about 3% of all colorectal cancer. And the reason why we define KRAS and RAS as different is because anti-EGFR therapies work in RAS wild type tumors, but they are not indicated for RAS mutant patients.

So this is the larger bucket of how we dichotomize colorectal cancer. Now coming to what we wanna concentrate on. And if you notice so far, you’ve heard the word MSI-high, you’ve heard the word mutations but when it comes to HER2, we are going to slightly shift gears. So HER2-positive colorectal cancer, when we say it’s HER2-positive colorectal cancer, what we are actually saying is it’s a HER2 overexpressed or amplified colorectal cancer.

So to go into some details regarding this, all proteins in the human body are coded by genes. There is a certain amount of protein in your body, and all of these proteins which are the HER family of receptors, EGFR, HER2, which is also called as ERBB2 HER3, HER4. This is a whole family of receptors that help normal growth and signaling in cells.

When it becomes abnormal, that’s when they cause cancerous growth or tumorous growths, right? So when you have HER2, it is the second member of that family. The first member of this family is HER1. It is also known as EGFR. And we know in colorectal cancer, EGFR axis is very active. This is the reason why cetuximab and panitumumab are used routinely for patients with RAS wild-type tumors.

And we know that in left-sided RAS wild-type tumors, anti-EGFR therapy combined with chemotherapy can significantly improve patient outcomes. We’ve also started recognizing that EGFR is so important for colorectal cancer that anti-EGFR therapy has to be combined with BRAF-targeted therapy, and it has to be combined with KRAS G12C-targeted therapy because if you target BRAF mutations and KRAS mutation as single agents it tends to amplify the EGFR signal And that’s how it bypasses that activity.

So single-agent BRAF and single-agent KRAS G12C, unlike lung cancer and pancreas cancer or other, or melanoma, doesn’t really work in colorectal cancer. So the reason why I’m harping upon that is to understand that this axis is actually very important in colorectal cancer. That’s EGFR or HER1. Now we are going to move to that second partner in that family, which is HER2.

It is also known as ERBB2. Unlike KRAS and BRAF, HER2 mutations are not very common in colorectal cancer, and when mutations occur, they often don’t occur in the activating regions of that protein. So lung cancer is a notable exception to this. Lung cancer is driven by HER2 mutations, and many of those mutations tend to occur in the activating domain of the protein.

So when we talk about HER2 positive lung cancer, we are talking about HER2 mutant lung cancer. But when we are talking about HER2 positive breast cancer or HER2 positive gastric cancer or HER2 positive colorectal cancer, we are actually talking about HER2 amplified or overexpressed proteins, right?

So what’s happening here at the genetic level is there are more number of copies of the HER2 gene than is normal. So when you have more copies of the gene, they produce a lot of protein. That protein comes to the surface of the cells, and that’s how you can measure it, and that’s why it’s called HER2 overexpression or amplification. You can measure these this is also important because you can measure these by different mechanisms.

Overexpression is measured by immunohistochemistry. It is a way in which you can tag the protein on the surface of the cells, and that’s how you know that something is overexpressed. It’s often referred to as zero plus staining, one plus staining, two and three plus staining.

Not that it’s critical, but three plus is the highest level. If you have that’s important, and we’ll come back to why that’s important. And then amplification can be tested by either ISH In-situ Hybridization) the terms commonly used in the clinic are FISH ( Fluorescent ISH) or or dual ISH or they can be tested by next generation sequencing platforms like Foundation Medicine, Caris, Tempus, Boston Gene, NeoGenomics.

Because what all of these profiles are doing is they’re looking at the DNA, and they’re actually giving you a count of the genes that you are seeing. The reason why this is important is because for most colorectal cancer patients, now that you know that you need to know the BRAF status, KRAS status, HER2 status, NTRK fusion, MSI high, NGS becomes the more obvious way of testing this, right?

Because it gives you the answer to all of these in one go. Immunohistochemistry has to be done separately for most and often cannot catch mutations. I think the long and short of this is that it’s very important for patients to recognize what is the testing that their providers are doing.

And as complex as the landscape of cancer is it’s even more important to know what your local oncologist is testing and what exactly is being tested by the platform that’s being used. So HER2 overexpressed or amplified, and you’ll see me calling this HER2 positive, so that’s why I spent some time on this, is whenever I say HER2-positive colorectal cancer, for all practical purposes, it’s HER2 amplified or overexpressed. When you do NGS sequencing many times my patients come to us saying, “I have a HER2 mutation.”

But then we have to figure out what kind of mutation it is and almost all the data in HER2 colorectal cancer has been developed in HER2 amplified overexpressed tumors, not mutant tumors. So this subset of colorectal cancer is seen in about 2% to 4% of all colorectal cancer. But when you look at that square, one thing that you recognize, most of these are RAS/BRAF wild-type patients, okay?

And this is a very important element of having HER2 amplification because it affects how you target HER2 at a later date. So HER2 overexpression and amplification tends to occur more in RAS wild type, but there are a small number of RAS mutant patients that can have HER2 amplification. So if your results turn out to be HER2 amplified or overexpressed, the first question you need to ask is which of those categories you fall into.

In RAS wild type patients it’s about 6% to 8%, whereas it’s only 1% to 2% in RAS mutant patients, which means 80% of all HER2 amplify- amplifications and overexpressions will occur in a RAS wild type tumor. Only 20% will occur in a RAS mutant cancer. The other way in which this cancer, this subset of colorectal cancer differs from all other subsets of colorectal cancer is its propensity for brain metastases. Colorectal cancer as an entity doesn’t classically metastasize to the brain.

This is the reason why in normal staging of colorectal cancer, we do not do MRI of the brain or CT scan of the brain. This is not the same story in lung cancer or melanoma, where there is a high risk of brain metastases, so MRI brain or h- imaging of the head is a standard part of their workup. But in HER2 overexpressed or amplified colorectal cancer, we have found that the incidence of brain metastases is h- as high as 20%, which is four times more than what’s seen in garden variety colorectal cancer.

In most colorectal cancer, the brain metastases prevalence is about 2 to 4%. This is a very key clinical area where we need to develop a very different outlook towards HER2 positive colorectal cancer in terms of the fact that we need to do some sort of screening for the brain metastases, i.e.Imaging of the brain. And we’ve found this out a lot of times when we have clinical trials that are requiring HER2 positive colorectal cancer, and we are doing MRIs of brain at, as baseline in clinical trials, which we don’t do routinely in clinical practice. We are seeing a lot of patients that present de novo with brain metastases.

This is not a story that’s restricted to colorectal cancer. HER2 positive cancers have higher propensity for brain metastases, even in breast, gastric, and other tumors. So we have to keep that in mind. So now going on to the fact that does HER2 really impact my treatment as metastatic colorectal cancer?

And the answer is yes. This is a busy slide, but basically what it is showing you is that there is the EGFR axis in colorectal cancer. This is a growth signal in colorectal cancer. It’s highly upregulated in colorectal cancer in general. HER2 is a part of that axis, and when you have lots of HER2, then you have increased signaling.

And the reason why this is important is because if you give these patients anti-EGFR therapy, which we do in a lot of our patients with RAS wild-type tumors, it’s unlikely to work because there is an activation in a cross pathway. So we looked at some of this data and we looked at patients who were treated with anti-EGFR with or without chemo and compared HER2 amplified and non-HER2 amplified colorectal cancer patients.

And what we found is if you were HER2 negative, you did better. Your progression-free survival was about eight months, eight to nine months if you were HER2 non-amplified. But if you were HER2 amplified the progression-free survival was under three months. So i.e., most patients got anti-EGFR and those with HER2 amplification had disease progression or growth in less than three months.

This is very critical because it is restricted to anti-EGFR efficacy, and it does not stand true for others. So BRAF, for example, is a very strong marker for you doing poorly on any chemotherapy, apart from the one where you combine BRAF inhibitors. But in HER2 this is only for anti-EGFR. So in our practice, we prefer not to treat patients that are HER2 amplified with anti-EGFR agents, at least upfront, and there’s a nuance to this which I will discuss in the subsequent slides.

So how do we target HER2 in metastatic colorectal cancer?

And there are various mechanisms by which we can target HER2 in in colorectal cancer. So the first one is this dual anti-HER2 therapy. If you remember the case that we presented, that was their first trial. Dual anti-HER2 therapy means you combine two anti-HER2 drugs. It can be either trastuzumab + tucatinib or trastuzumab + pertuzumab.

Trastuzumab is the age-old HER2 drug. This is used in breast cancer, gastric cancer. And then pertuzumab is a monoclonal, another antibody against HER2. And tucatinib is what is called as a tyrosine kinase inhibitor. These are small molecules, so they can go inside the cell, and they can shut off the activating part of the HER2 protein. But bottom line, you have to combine at least two drugs together, or at least that’s what the data shows.

The second class of drugs is antibody drug conjugates. These are antibodies like trastuzumab, but what you’ve done now is you’ve loaded this with a cytotoxic chemotherapy. And in this case, that cytotoxic chemotherapy is deruxtecan which is like a cousin of irinotecan, which is used in colorectal cancer. We know it has activity. Unfortunately, we are never able to deliver enough topoisomerase I poison, which is the class of drug this is, because the toxicities intervene. So now, if you can target that cytotoxic chemotherapy only to the cancer cells, you have a larger therapeutic window which means that you can probably do more damage to the tumor and less damage to the rest of the body.

These are antibody drug conjugates. The two antibody drug conjugates that we are gonna talk about is trastuzumab deruxtecan and JSKN003, while there are other antibody drug conjugates that are being developed in this space. So stay tuned for that.

And then there is a third class of antibodies called bispecific antibodies, and this basically means that the antibody binds two targets.

Zanidatamab is a bispecific antibody that binds HER2 at two different spots. So in a way, it’s one drug, but it works like a dual HER2 target, right? Because what it’s doing is it’s binding two different areas on the same proteins. Very much similar to what trastuzumab and pertuzumab, which are two different drugs, would do together. Zanidatamab does that as a single agent.

And then there are some HER2 T-cell engagers that are being created These are immunotherapy drugs, and their antibody has one one element that binds HER2, and then one element that binds CD3, which is a molecule on your T cells or immune cells, and they bring them together to cause the cytotoxic effect of those T cells on the cancer.

So these are T-cell engagers, and there are a bunch of those that are being developed in in HER2. Barring this, there are multiple combination chemotherapies. Zontivantnib is a very interesting HER2 tyrosine kinase inhibitor, so very much similar to tucatinib. It’s a small molecule. It’s a pill.

But some of the early data is showing that while tucatinib or trastuzumab or pertuzumab don’t work as single agents in this disease, zontivantnib, even as a single agent, has significant activity in metastatic colorectal cancer, and this is a widely developing field, and we’re very excited about it.

But there are other combinations, and in addition to this, there are multiple HER2-directed CAR T-cell therapies that are being developed. They’re in early phase of development. So I’m gonna review some of the data that that supports the use of those strategies. And these are a little bit busy slides, but I’ll try to walk you through each one of them.

So first, we’re gonna talk about dual anti-HER2 inhibition. If you remember from this slide basically what you’re doing is you’re combining two HER2 drugs. This is Trastuzumab Tucatinib. This was done as a part of the MOUNTAINEER study. Patients were refractory to their standard lines of treatment, so they had already received two or more than two lines of treatment, and they had progressed through it.

Remember, all of these were RAS wild type because in RAS mutant, it’s your RAS mutation that’s the driving force not HER2. So if you give these drugs in a RAS mutant patient, it’s not going to work. So these dual anti-HER2 therapies are these dual anti-HER2 therapy agents are effective in RAS wild type HER2-amplified tumors not in RAS mutant.

Okay? So they treated a bunch of patients with both the drugs, and they also treated a few patients with single drug, right? And this is, remember, we talked about it, why dual? Why not just single agent? And this is a very important question that you need to ask your provider if they are suggesting this.

The primary endpoint was response rate, so the ability to ability of the drug to shrink the cancer for more than thirty percent. And what they found was when you combine the drug together in a patient population that has already received two lines of treatment, it was thirty-eight percent response rate.

So thirty-eight percent of patients responded, and the median duration of response was huge. It was almost ten months in this in this group and nearly seventy percent of patients had at least stable disease, right? So this is a very effective treatment because remember, all these patients if they don’t get HER2 drugs, their only other options are Bev and TAS-102 or Fruquintinib or Regorafenib, and the response rates for all those drugs is less than five percent.

So knowing that you have a thirty-eight percent response rate and also not just a good response rate, but also a long-lasting response rate tells you that this is a very effective treatment based on the results of the MOUNTAINEER study. Now Trastuzumab and Tucatinib is not only FDA- approved combination in this population, but also on the NCCN guidelines.

In contrast please note that there were a few patients that got only tucatinib, so only one HER2 drug, and their response rate was 3%, which means that this is not effective as a single agent drug. It has to be given in combination. And what the study allowed was when patients progressed on single agent, it allowed them to get both the agents, and even then the response rate was only 17%.

So it never reached as high a response rate as it got when you gave it upfront. So this is critical. For RAS wild type HER2 amplified tumors, trastuzumab and tucatinib should be given upfront meaning after two lines of treatment.

The next is trastuzumab/pertuzumab. There’s no big difference between these two.

There is no head-to-head comparison. Trastuzumab/pertuzumab is also on the NCCN guidelines. Very similar trial. These are two monoclonal antibodies, so they’re both IV drugs rather than trastuzumab/tucatinib, which is one IV, one oral drug. The reason why I bring this study up is it taught us a lot about HER2 amplification and how HER2 therapy works.

So if you remember in the slides I told you that HER2-amplified patients don’t really respond very well to anti-EGFR, but what we found is that unlike mutations, which is a yes and a no answer amplification occurs on a spectrum. So more number of HER2 genes you have, the more addicted your cancer is to HER2, and therefore the higher likelihood that it will not respond to anti-EGFR and the higher likelihood that it will respond to a anti-HER2 therapy.

So when you look at your gene copy numbers, which is what we looked at here. If your gene copy numbers were greater than 20, your response rate to this drug is nearly 60%, whereas if it’s less than 20, the response rate is 10%. And when your gene copy numbers are low, you actually do respond to anti-EGFR drugs. So you respond like 40% of the times, whereas if it’s high, you do not respond. So this is a very critical element to keep in mind that you don’t only ask the question, “Am I HER2 positive?” You also ask the question, “Am I RAS wild type? Am I RAS mutant?” And more importantly, “What is my gene copy number? How high is my amplification?” If it’s really high, then the chances of responding to a anti-HER2 therapy definitely increase

Now we are going to go to antibody drug conjugates. This is Trastuzumab Deruxtecan. This has been approved in in colorectal cancer and actually this is an approval for any HER2 positive tumor. So it’s a pan-tumor approval. This drug was tested in a phase two study, heavily pre-treated population. In fact, some of the patients were already pre-treated with a dual anti-HER2 or HER2 therapy before. So they had already received HER2 therapy, but they were still HER2 positive. So one of the key things is when you get HER2 therapy, sometimes you can lose HER2, so you have to re-biopsy or do circulating tumor DNA or blood work to assess that you still are HER2 positive.

But if you are HER2 positive, this IV antibody drug conjugate in a large group of patients showed a response rate of nearly thirty-eight percent. So very similar to dual anti-HER2 therapy. The key element here was it actually works in RAS mutant colorectal cancer. So that small segment of patients who are HER2 amplified and have RAS mutant, they cannot get dual anti-HER2 therapy, but they can get antibody drug conjugates, and they would still respond to it with a median overall survival of nearly sixteen months.

It was a highly active regimen and works in patients who’ve had prior therapy, just like our case that we presented earlier, which highlights the importance of the fact that you can sequence these agents and get good mileage out of these agents together. So this is Trastuzumab Deruxtecan, And then we come to zanidatamab very similar to-

[00:32:03] Manju George: Dr. Raghav, can I ask you a question? Does the amplification level matter for the previous  T-DxD?

[00:32:11] Dr. Raghav: Yeah, so absolutely. Because. So remember the way this drug works is it’s not inhibiting the axis or it’s not inhibiting that growth signal. What it is doing is it’s using HER2 as a homing beacon for the chemo.

So in the analysis what we have seen is when you have HER2 3+, which is the highest protein expression of HER2, your response rates are as high as 50%. But if it is 2+, then your response rates fall down dramatically, and the response rates there are somewhere between 8 to 10%, right? So again, that’s a great question, Manju, is you shouldn’t just ask how much protein, Am I HER2 positive in terms of my protein, but also ask, like, “how strong is my protein expression?” And if it’s 3+, then you have a great chance of responding to this this agent. Zanidatamab, we talked about how this is a bispecific antibody that binds on two different areas on HER2, so it works like trastuzumab, pertuzumab.

And you can see that in a large group of patients that were colorectal, highly treatment refractory, response rates of nearly 38%, very similar to the response rates seen with trastuzumab, pertuzumab, and trastuzumab deruxtecan.

While we have made a good dent in HER2 positive colorectal cancer we have now multiple active treatments. Two of these treatments are actually on the NCCN guidelines, and both of which are FDA-approved currently. As you’ve seen, somewhere between 30 to 50% patients are benefiting from these drugs initially. But there’s a large scope of improvement. So the next series and next generation of trials are being designed to answer questions that can help more and more patients for HER2 and also in different settings.

One of the first trials is MOUNTAINEER-03. This is a trial which is trying to take trastuzumab and tucatinib, which is the anti-HER2 therapy, dual anti-HER2 therapy, to first-line setting and seeing whether combining this with the standard of care chemo is better than combining chemo with any other drug like bevacizumab or cetuximab, which are anti-EGFR and VEGF agents and are currently the standard of care in first line.

And this study is currently ongoing. We have to enroll 400 patients to this study. You can imagine this is a rare subset. So if patients have HER2, one of the first things that I would always request is once you have a rare subset of a common cancer, you should be managed by people who know how to handle that subset, and we should always be looking for clinical trials because we can improve your outcomes better than the standard of care. So this is a clinical trial. The primary endpoint is progression-free survival. This study is ongoing, and we are excited and and looking forward to the results of this study. Hopefully, this can change the the first-line landscape for colorectal cancer.

The other trial that is being done is for JSKN003. This drug is an antibody drug conjugate, very much like trastuzumab deruxtecan. In the early phase studies, it has shown a response rate of nearly 60%. Just compare that to standard third line chemo, which is regorafenib, fruquintinib or bev-tas, which is less than 5% conservatively. And therefore, this drug is now being tested in a phase three trial where patients are being randomized to either the drug or investigator’s choice of chemotherapy, which is a non-anti-HER2 therapy. Progression-free survival is the key and I think, this study has just recently started. Along the same lines, there are other clinical trials that are being adopted for other ADCs and anti-HER2 therapy in first and second line settings.

[00:36:22] Manju George: Dr. Aggarwal- Yeah was that on the first line or it’s like third?

[00:36:26] Dr. Raghav: This is third line. Okay. This is third line. Yeah. Because we are comparing them to regorafenib, furkutinib or bev-tas. So this is a third line study. Zanidatamab has a bunch of different trials that are currently being done. One of them is first line.

These are not randomized. The first two trials were randomized trials. This is zani combining with chemo and and/or bevacizumab. This is in first-line setting. There is another Phase 2 study, which is a HER2 pan-tumor study, which allows colorectal cancer patients that have progressed on at least one line of therapy.

This is a monotherapy cohort. And then there are some hints of activity in even HER2 mutant colorectal cancer, but only specific types of mutations. So we’re testing it in HER2 altered solid tumors other than amplification and overexpression because those will form the first two studies.

So those are some of the key trials, but there are many others. I just wanted to highlight some of these. And then the future here is combinations. Zongertinib, we talked about this. This is tucatinib, but it’s showing single agent activity in HER2 positive colorectal cancer.

There are, trials for this in combination with both ADCs and chemotherapy. There is a trial that we did, which is combining the ADC with a drug called ceralacertib. This drug actually increases the sensitivity of the drugs to the chemotherapy. So it doesn’t affect HER2 in any way, but it increases the sensitivity, and this is one of the combinations in trying to see if we can increase the response rates in the HER2 low patients that are not as high as HER2 3 plus, and even in HER2 3 plus, increase the duration of response and the depth of response.

And then there are some trials that are combining HER2 therapy with immunotherapy as has been done in gastric cancer with very good outcomes. Stay tuned for some of those. Coming to this I’d like to wrap up because I’d like to leave some time for questions.

What are the key takeaways for HER2 positive metastatic colorectal cancer in this space? HER2 overexpression or amplification, which is HER2 positive colorectal cancer, is seen in about 2% to 3% of all colorectal cancer, but it’s enriched in RAS/BRAF wild-type tumors. Dual anti-HER2 inhibition is effective in this population.

And then HER2 ADCs have shown promising activity in this population, along with those that have been treated with dual anti-HER2 inhibition, along with those that have actually RAS mutant HER2 positive colorectal cancer. HER2 ADCs have shown promise in that. HER2 testing can be performed through various mechanisms, but the question that a patient should know about their HER2 status is, “Am I HER2 positive or negative?

If I’m positive, was I tested for protein or just the gene? If I was tested for protein, how high is my protein expression? If I was tested for gene, how high is my gene expression?” And most important of all, the moment you come to know about this consider early reference to centers that are running clinical trials in HER2 disease.

I think we have come a long way, but there’s still a long way to go. And clinical trials are the only way we can reach there and this is a good time I’d like to put in a shameless appeal to our patients and caregivers about trying to make sure and encouraging not just themselves, their family members, but also other patients that they come in contact with who have HER2 positive disease and for that matter, any molecular subset of colorectal cancer towards clinical trials. So I’m gonna stop there and and see if you have any questions.

Thank you, Manju.

[00:40:18] Manju George: Okay. Dr. Raghav, thanks a lot. We’ll open the session to questions. Please type your questions in chat or use the Q&A feature, and then we can bring those up. So maybe I can start, Dr. Raghav. I’ve heard that HER2 amplification is a little bit more common in rectal cancer.

Do you have any comments? So for rectal cancer patients what advice can we give?

[00:40:45] Dr. Raghav: Yeah. I definitely think that so HER2 is seen more on left-sided tumors than on right-sided tumors. Right-sided tumors also tend to be higher MSI, higher BRAF, and those are patients that don’t have HER2 amplifications.

And, obviously rectal is area where you see a lot of HER2 amplification. Again we do not approach that any differently as of today compared to HER2 positive colorectal cancer. But my hope is that at some point of time, targeted therapies would come to have a home in this total neoadjuvant therapy approach that we take towards rectal cancer, which is doing most of our radiation and systemic therapy prior to surgery and sometimes even as a surgery-sparing approach, right?

So I do feel that there is a value in looking forward to those analysis and tests, but currently it’s not treated any differently from a HER2-positive colon cancer.

[00:41:43] Manju George: Okay. And then especially for patients those ones who have, say, locally advanced rectal cancer, and they had TNT, and they either had surgery or had non-operative management, and then they progress to Stage 4. For them, testing also becomes a little bit complicated because they probably don’t have tissue from the earlier, situation. So in such cases, maybe their only option is to get a liquid biopsy if- the metastatic sites are not easy to biopsy, right?

[00:42:13] Dr. Raghav: Yeah.

[00:42:13] Manju George: That also adds a layer of, how do you know what to test and all of that, right?

[00:42:20] Dr. Raghav: Yeah. I agree, Manju. I think that this is a key area. Although I am a firm believer of the fact that that tissue should never be a limiting issue in metastatic disease. First of all, there are very few patients that cannot safely be biopsied. There is a nuance. I think circulating tumor DNA is really useful- as a non-invasive measure, but it has its limitations compared to tissue testing. And more so in amplifications than in mutations because you have to actually measure the copy numbers, and it would depend on how much your tumor is contributing. So if you have really low volume disease, your sensitivity for circulating tumor DNA also goes down.

Okay. So I feel that with all the advances that we have made in terms of our biopsy capabilities– CT guided, ultrasound guided in the larger scheme of things for most of our patients that are dealing with a life-altering, life-limiting disease, a lack of biopsy should only be an exception, not the rule.

[00:43:28] Manju George: Yeah. Okay, that makes a lot of sense. So the other question I have is you said that when there is HER2 amplification and patients are put on EGFR directed therapy they have a faster progression. So do you think that because a lot of patients don’t get tested for HER2 specifically, many of them may get tested for KRAS and MSS, MSI-high, would you suggest that if you see patients having that fast progression on EGFR inhibitors, would that be another point to say maybe you should try to get tissue testing?

[00:44:03] Dr. Raghav: Yeah, absolutely. I think, if it’s happening, you should do it. Although I would go one step beyond and say at least in my practice, I would feel extremely uncomfortable and and for a lack of better word, negligent if I did not do comprehensive molecular profiling- on all my patients before starting therapy. ‘Cause, more and more evidence is showing now that we have carved out these subsets in colorectal cancer, and there is no excuse for not determining your colorectal cancer subtype before you move into the therapeutic landscape.

Because of not just how you determine clinical trials and the trials that you can get early into, but also clinical outcomes can differ significantly. I would not want to start any patient on first-line therapy now absolutely without knowing their MSI and BRAF and RAS status, ’cause it determines what it is.

Their HER2 status also determines whether you can get onto a clinical trial. But the point is, if you need all of those three things, most likely you’re going to get an NGS sequencing for that, and you should get your your HER2 analysis, or at least the amplification analysis from that. So I like that question because it tries to problem solve. But I also don’t like that question because I don’t think it should be a question in treating colorectal cancer in 2026.

[00:45:41] Manju George: Yeah. Yeah, I agree. I agree. And then the other point you made about brain mets is would you look at HER2 or would you be thinking about testing for HER2 if a patient is diagnosed initially with brain mets? Or- is there a time point ,do HER2 amplified tumors develop, people with those tumors develop brain mets along the course of their disease?

[00:46:04] Dr. Raghav: So they can develop it along the course of their disease, but there have been a lot of patients that we’ve put on clinical trials where we did the MRI testing upfront because it was required by the protocol, and we found de novo metastatic disease.

So- Okay … when you treat somebody for six months or nine months, and then all of a sudden you have brain metastases, how would you know whether this is something that developed during the course, or was it already present? The way it has changed my clinical practice is now if I have HER2 positivity, I will always do imaging of the brain prior to starting any treatment because I don’t want to be blindsided by a new brain metastases, two or three months down the line. Because then I would have no idea whether the HER2 treatment was working, not working, or what was going on.

[00:46:46] Manju George: Okay. Okay, that makes sense. And then do all these drugs the ADCs, the bispecific antibodies, all of them, do they cross into the brain?

[00:46:53] Dr. Raghav: Great question. So there is some data that the TKIs and the ADCs actually do have intracranial activity.

[00:47:01] Manju George: Okay.

[00:47:01] Dr. Raghav: So we actually treat with anti-HER2 drugs for some of these. And sometimes we can avoid radiation, especially if they are a small size and relatively asymptomatic.

[00:47:11] Manju George: Okay. And then so in COLONTOWN we have the HER2 clinic is what we call. It… That’s for patients who know their HER2 or ERBB2 status. But we also have a group for brain mets, and I’m wondering whether it might be of value to to tell those patients that if you have brain mets and you don’t know your HER2 status, maybe there is a point in making sure that the tumor has been checked for HER2, right?

[00:47:37] Dr. Raghav: Yeah. That’s a great point. Yeah. Couldn’t agree more

[00:47:40] Manju George: Yeah. And then the other question is there is a first-line MOUNTAINEER 03 trial, right? So what about patients who are already on second line now and they missed the opportunity to participate in that trial? How would you treat such a patient in your practice?

[00:47:57] Dr. Raghav: For me, in my practice, second line would be an anti-HER2 therapy.

[00:48:02] Manju George: Okay.

[00:48:03] Dr. Raghav: Depending on how high their copy numbers are and how high their protein expression is. And also clinical trials would be the number one thing. I just do have to remind everyone that while we’ve made significant progress, there is still more progress to be made, so I’m hoping that there will be more newer clinical trials and more clinical trials in this space.

[00:48:26] Manju George: Okay. So what you’re saying is that you would prefer to put them in a clinical trial second line if that’s possible. Otherwise, you will give a HER2-targeted therapy. But would you give Trastuzumab tucatinib? Or would you give a the traustumab deruxtecan, like TDX-D?

Or, how would you decide which one to give?

[00:48:47] Dr. Raghav: Yeah, so that’s a very interesting question. I think it depends on multiple factors. For example, if somebody is KRAS mutant and HER2 amplified, you can only get ADC, Okay. If you have a really high HER2 expression but your gene copy numbers are, unclear or in- intermediate, then, you could potentially think about ADCs to start with.

There is also growing literature on some of the resistance mechanisms to dual anti-HER2 therapy, like presence of concomitant HER2 mutations, PIK3CA mutation. If you have these along with HER2 amplification, you are less likely to respond to those, so those are patients that I might move towards an ADC.

But let’s say everything is good for a dual anti-HER2, then I prefer to do dual anti-HER2 before HER2 ADC for two reasons. Number one, the toxicity profile is better. The duration of response is better for dual anti-HER2. But more importantly, I have data that HER2 ADCs will work even in patients who have progressed on HER2 dual anti-HER2 therapy, but I don’t have the data the other way around, right?

[00:49:59] Manju George: Okay. Okay.

[00:49:59] Dr. Raghav: So I think that’s usually the sequencing with the with some nuances as I pointed out.

[00:50:05] Manju George: Okay. So you would put them in a trial if you have one, and if they progress on that, then you will go to dual HER2. And then once they progress on that, then you will go to ADC.

[00:50:17] Dr. Raghav: Our trials are usually HER2-directed trials, so I would like to put them on a HER2-directed trial.

[00:50:22] Manju George: Okay. Okay. That would be your first choice. But if people are at centers where they don’t have a HER2-directed trial-

[00:50:30] Dr. Raghav: Yeah. Yeah, dual ,and then ADCs.

[00:50:32] Manju George: Okay. Okay.

[00:50:33] Dr. Raghav: With few exceptions.

[00:50:35] Manju George: Okay. And then you have the, phase one those trials. Is it okay if you can go back to those slides?

Would it … Is there any, Serlasertib or something.

[00:50:46] Dr. Raghav: Serlasertib, yes.

[00:50:47] Manju George: Yeah.

[00:50:47] Dr. Raghav: Serlasertib, yeah. So

[00:50:48] Manju George: you have a few different strategies on that slide, right?

[00:50:52] Dr. Raghav: Yeah. So I think that those are all clinical trials, but they’re all clinical trials of a HER2 therapy that is showing efficacy very equivalent to what we have as standard of care- Okay

but trying to add something more.

[00:51:05] Manju George: Okay. Okay.

[00:51:06] Dr. Raghav: And to me, adding something more is required. Okay. Because I am not satisfied with 38% response rate. Okay. I want it better, right?

[00:51:15] Manju George: Okay.

[00:51:15] Dr. Raghav: So as long as there is a combination, I would always go for the combination because I want to improve that outcome even further.

[00:51:22] Manju George: Okay. Okay. And between them if you have a patient who’s looking for trials, would you suggest go for this one versus that one? Or whatever is open and whatever is … Any of them should be good enough?

[00:51:34] Dr. Raghav: I think any of them is better than the other. There may be some advantages of doing one over the other.

[00:51:42] Manju George: Okay.

[00:51:42] Dr. Raghav: But I think that’s a very in-depth discussion. You may require some insight into how their immunity profile is, what’s available. But just remember, while we are trying to, have more and more trials, there is still a limit of how many patients are on those trials, where they are.

So I think a trial is always better than no trial in my opinion. And and whatever you have access to it also has to take into consideration patient’s quality of life, their their logistical issues that affect their, day-to-day life. So I think, most of the times when I choose between trials there is some scientific basis to it, but majority of that is a non-medical, reason. Like how frequently do they have to come, how much they have to travel, does it require inpatient admission and so on and so forth.

[00:52:37] Manju George: Okay. Thank you. I don’t see any Q&A questions, … And we are at time. So thank you so much for this very exhaustive talk on targeted therapies against, HER2 amplification.

And it was a pleasure to have you, and a recording of this video will appear on COLONTOWN University within about two weeks. So thank you again.

[00:53:01] Dr. Raghav: Thank you, Manju. It was my privilege.

[00:53:03] Manju George: Take care. Yeah. Thanks to everyone who attended the talk.