Antibody drug conjugates in CRC: Dr. Raghav (2021)

Manju George 0:01
Hi everyone. Welcome to Doc talks. I’m Manju George, the Scientific Director of COLONTOWN. Today we have with us. Dr. Kanwal Raghav. Dr. Raghav is an associate professor in the Department of GI Medical Oncology at MD Anderson, and the Medical Director of the Division of Ambulatory treatment centers at MD Anderson. He obtained his MD from Albert Einstein Medical Center and completed clinical hematology and oncology fellowship from MD Anderson. So Dr Raghav welcome. We are excited to have you with us.

Dr. Kanwal Raghav 0:33
Thank you, Manju, for having me. I’m really excited by this particular talk. I’m sure that the audience is already aware of a lot of developments in this field but this is one of the more newer treatment strategies that we haven’t yet explored in colorectal cancer. And essentially, the topic is centered around antibody drug conjugates in colorectal cancers, Prospects and pitfalls. So our agenda, essentially, is to look at some of the ADCs that are being developed in colorectal cancer, more specifically, trastuzamab deruxtecan, which is the newly approved antibody drug conjugate in breast as well as gastric cancer, not yet in colon cancer, and then review some other ADC’S that are in development and and some of the unmet needs for our colorectal cancer patient population. So a quick, review of why this is still an important and unmet need. About 150,000 cases a year, in 2020 and 8%of all cancers, and 53,000 deaths, and again, about 9% of all those deaths which is a which is a significant burden of cancer care in the United States and almost across the world. And one of the issues is that, despite our screening measures and other aspects, you can notice that, localized disease are confined to the primary site is still seen in only about 38% population. A large number of patients will have disease that has already spread to their lymph nodes or to other organs. So locally advanced or regional disease, as well as distant metastases and the problem with this is that even if you have stage III disease, the chances of recurrence can happen, and therefore the total patients who have metastatic colorectal cancer is a high population, and therefore need adequate treatments. And when you look at the five year survival, it’s not very optimistic, because our five year survival for metastatic disease is still teetering around 15 to 20% despite our advances in systemic therapies. Now, hopefully that will change with certain new developments that have taken place. But for now our overall survival outcomes require significant improvement, and you can see that that five year survival rate has slowly and steadily increased, but not as much as we had really hoped for or we would really like to strive for.

Dr. Kanwal Raghav 3:42
So the current standard of care for any colorectal cancer, metastatic colorectal cancer patient is either chemotherapy, and that chemotherapy can be given as a single drug, a double drug or triple drugs, depending on various patient and disease factors. Two biological biological therapies, anti-VEGF,drugs like Bevacizumab, aflibercept, Ramucirumab, anti-EGFR, drugs like Cetuximab or Panitumumab, targeted therapies against BRAF, targeted therapies against HER2, immunotherapy for MSI high colorectal cancer, which is pembro-nivo with or without, ipilimumab, and then two salvage therapy drugs, Regorafenib and TAS 102. But if you think about, on the surface, it looks like we have a lot of options, but then you actually drill down into the details of this, what we find is that we are lacking intherapies for a vast majority of patients. So. If you think about Pembrolizumab, nivo and nivo IpI, which has been perhaps the greatest benefit in terms of survival for our patients, almost to the tune of calling cures and few patients that is exclusively restricted to an MSI high population or a deficient mismatch repair population. So people who have repair defects in the mismatch repair proteins, and this is about 4 to 5% of our population. So in metastatic settings, so again, a small subset, then, response rates close to 45-55% in that population. Again, that does not mean that we do not need to work hard on that subset, because there are still about 50% patients that do not benefit from immunotherapy despite having an MSI high tumor. Then comes the story of BRAF, again, very, very encouraging that for the first time, a randomized trial has shown benefit in this highly aggressive population. But this population amounts to, again, 7 to 8% of our total population, and even within that population, response rates are about 20% with the Beacon treatment regiman. So again, lots of scope of improvement. Then comes Larotrectinib or entrectinib, which are drugs for NTRK fusion. These fusions are extremely rare in colorectal cancer, less than 0.5%. Great response rate [with these drugs]!. But again, a very small subset of the population. And last but not the least is HER2 which is present in about 2 to 3% of our population. Again, multiple treatments, available response rates still around 30 to 50% so the bottom line of the slide is that we have made some advances which are encouraging in in a select subset, a small subset of our population. A large majority of our patients still do not have treatment options, and even within all these targeted therapies, there is a great scope of improvement, because we really have not made [as much progress?]. So one of the questions, which almost invariably comes up with the patients and provider groups that we talk to is, what would be your recommendations? And our recommendations are always trying to strive towards clinical trials, because, clinical trials will form the basis of whatever approvals that happen. And in this large group like the HER2, we don’t have a single approval as yet, right? So patients are often subjected to the mercy of the pairs in the market, and the physicians that are are willing to work to get these drugs off label. So still, a great way to go in the HER2 and I’m going to concentrate on that HER2 space for now. So here in comes this new strategy.

Dr. Kanwal Raghav 8:19
So for now, we have only two strategies in colorectal cancer, which we’ve seen. It’s either chemo drugs or targeted therapy/ immunotherapy, considering immunotherapy is a targeted therapy for a subset of population. Now here comes the ADCs. And ADCs are not new. These antibody drug conjugates are not new. They have been the first ADC approval by the FDA in 2000 which was Gemtuzumab, which was against the CD3 positive AML. So in short, if you think about an ADC–an ADC strategy involves finding a target and then giving chemotherapy that can attack that target. So again, if you broadly think about it, you can either give a chemo drug systemically through IV that we usually give. You can either give a targeted drug, provided that alteration is actually driving the cancer, such as BRAF mutant colorectal cancer. But there are lots of molecules on the surface of cancer cells that don’t really drive the cancer, but they are selectively expressed in that cancer. So ADC is what they do, is they try to exploit that target, and they create a kind of a homing beacon or a smart bomb, in which you can attach a very highly potent cytotoxic chemical, which you otherwise wouldn’t be able to give somebody IV because of their systemic toxicities. But you put that in the antibody, that antibody goes to the cell, the cell gets engulfed and destroys the cancer cells selectively. That’s the general principle of ADC, and this has been exploited in liquid tumors, like AML, Hodgkin’s lymphoma with CD30, where 90% of them express that CD30 molecule. In solid tumors, The first approval came for TDM1, or AdoTrastuzumab. This has, this has been the backbone of HER2 breast cancer therapy for a long period of time, since 2013

Dr. Kanwal Raghav 10:34
There were other approvals like inotuzumab, which is in CD20 ALL. Now you can see majority of them tend to be liquid tumors, and the reason is because most of the times those those cell surface, those cell surface proteins, are expressed selectively in those tumors, but not elsewhere in the body. But fortunately, in the last two years, there have been two new developments of ADCs and breast cancer, trastuzumab deruxtecan which for HER2 breast positive breast cancer, and second sacituzumab govitecan in triple negative breast cancer, which is against a different protein called TROP2 and this one is against HER2. So as you can see, a lot of development and solid tumors outside of colorectal cancer and we are trying to bring these developments into the realm of colorectal cancer. And as you can understand this, breast cancer is probably one of the attractive targets for industry because of the prevalence of these biomarkers. So, we’ve already talked about what an ADC does, right? So one obvious question that comes to mind is, if ADCs have been there for the last 20 years, why not in colorectal cancer? Do they not work in colorectal cancer? What’s the issue? The answer to that question depends on the technology. So the technology for ADCs has continuously been improved. So if you think about it, what happens with an ADC is the ADC binds to their antigen on the surface, then it gets internalized. When it gets internalized, it releases this payload, which is the cytotoxic compound or the or the chemo inside the cell, and that chemo destroys the cancer cell from within.

Dr. Kanwal Raghav 11:53
So the ADC activity depends on multiple factors. Number one, how commonly is your antigen expressed on the surface ? HER2 is a great example in breast cancer, where you have a good prevalence of this. And therefore they were tested in breast cancer, but in colon cancer, HER2expression is relatively low, therefore ADCs were never attempted to be developed in that space. Then it also depends on the payload. So T-DM1, for example, the first HER2 ADC to be approved, the payload acts against the microtubule environment. And we know that these microtubule inhibitors really don’t work very well in colon cancer. So that was one of the reasons why TDM activity is quite limited in colorectal cancer. Moreover, previous ADCs had very small drug to antibody ratio. So the antibodies is the compound to which you’re attaching the drug. And just to give you an example, T-DM1, which is a earlier generation ADC, only has two cytotoxic drugs attached to each antibody. But the newer drugs, like trastuzumab deruxtecan have as much as 7.8 drug antibody ratio, so really high levels of drug being delivered per antibody molecule. So all these characteristics have improved as the technology has improved. That is why you see about two to three approvals of ADCs in the last two years, which has not been the case in the past.

Dr. Kanwal Raghav 12:44
So again, we were talking about the things you need for an ADC to work: is you should have an antigen that is selectively expressed in that cancer. You should have a good antibody so it can attach properly. You should have a robust chemotherapy agent and also a high amount of that agent for the drug to be effective. And then the last thing is initially, most of the ADCs were non-cleavable ADC. So basically what used to happen is they used to go in the cells, and they get cleaved only inside the cells, and then they cannot go to a different cell. So if you have two cells, one which expresses the target and another which doesn’t express the target, it will only destroy the one that expresses the target. Fortunately, with cleavable chemotherapy agents and linkers, and also they are permeable, so what happens is the drug enters this cell, destroys the cell, and then percolates into the surrounding cells, creating a kind of a bystander effect. This is very important, because we know that one of the major resistance reasons of ADCs is tumor heterogeneity in which some cancer cells express the marker and other cancer cells don’t express the marker. So this bystander effect is a good way of getting around that.

Dr. Kanwal Raghav 16:04
So going to this, this ADC bystander effect. This is very clear from these molecules in which they took a HER2 positive and a HER2 negative line, and you can see when you look at these green markers, which is T-DM1 which is an older generation ADC, and DS-8201, which is a newer generation, ADC, when you look at HER2 positive, they both work. The green works and the red works. When you look at HER2 negative, they both don’t work, because there is no marker. But then when you mix these tumors, T-DM1 doesn’t work, but DS-8201 continues to work because of this bystander effect. And this is a great development in the field, because the tumor heterogeneity aspect is something that has been very challenging with ADCs. So in colorectal cancer, ADCs have been experimented with. And I’ll take the oldest ADC first, which was T-DM1. This is a non-cleavable linker. The drug antibody ratio is two, and it inhibits the tubulin microtubule system. And basically, when you looked at this NCI MATCH study for T-DM1, you found that there were lower GI malignancies, and you had some shrinkage, but not a whole lot of shrinkage with T-DM1, and you can see this is lower GI, lower GI, lower GI, lower GI. Here some stable disease. You can see, even though these are more than 30% response, it still looks like it’s a stable disease. So response rates of less than 10% with T-DM1 and therefore I do not recommend using T-DM1 in colorectal cancer patients, at least for HER2 amplification. Remember, all of these were HER2 high tumors, so they had lots of HER2 expression on the surface.

Dr. Kanwal Raghav 18:20
DS-8201, which is the latest ADC in this space, has all the good factors that we’ve discussed. So the payload is actually DXd, which is a topoisomerase inhibitor. Topoisomerase is an enzyme that is useful in DNA integrity, and one of the common drugs that we already use in colon cancer, which is irinotecan, is a topoisomerase inhibitor. So we already know that topoisomerase inhibitors work in colon cancer. DXd, which is the payload, is actually more potent than irinotecan. It’s about three to four times more potent than irinotecan. And one of the reasons why irinotecan is limited in efficacy in colon cancer is because when you give topoisomerase inhibitors in systemic circulation through IV, bone marrow suppression and diarrhea become limiting toxicities, so you cannot give a high enough dose to bring the absolute response. So the ceiling of the response is not driven by the drug, it is actually driven by the toxicities of the drug. So this compound is more potent and more selective because it’s not going into the systemic circulation. It’s actually going into the tumor tissue. Therefore, you can actually deliver a super high dose of Irinotecan, so to say, than you would have been able to deliver systemically. Also the drug antibody ratio is eight compared to two for T-DM1. The systemic half-life is very short, so the moment that drug gets released into the systemic circulation, it vanishes, and the side effects or systemic toxicities are minimal and then it’s membrane permeable, so creates that bystander effect, which we talked about, whereby it can affect tumors which are not HER2 high expressing.

Dr. Kanwal Raghav 20:36
So this is the study that evaluated DS-8201, in colorectal cancer. Just remember, DS-8201, has already been FDA approved for breast and gastric cancer. One of the things that I always like to put a disclaimer out for is– FDA approval does not mean that every patient will benefit from that drug. FDA approval does not mean that that is the end of research, and I think we should stop seeing that from this perspective, because especially for these rare subsets of patients, whereby if we don’t participate early on in clinical trials, we will never be able to improve upon the outcomes that we’ve already established. So just keep that in mind throughout this talk. So DS-8201, was studied in DESTINY CRC01 study, this was a study of metastatic colorectal cancer patients who had progressed through almost all standard lines of therapy. Regorafenib and TAS 102 were not required on this study, but response rates of those drugs is limited, and therefore referral to a clinical trial is not inappropriate. These all patients were RAS and BRAF wild type because HER2 expression is mostly seen in RAS /BRAF wild type tumors. It can also be seen in RAS mutant patients, and I’ll come back to that question in a bit. Most patients have received at least two lines of treatment, which is a considerably refractory colorectal cancer population. Prior HER2 therapy with other HER2 drugs was actually allowed. In this case, trastuzumab+ Pertuzumab, trastuzumab+lapatinib, trastuzumab+ tucatinib . Those are the three drugs. And just a word of caution there. There is clear data to suggest that dual anti HER2 therapy works in colorectal cancer, but single agent anti HER2 therapy is not very effective, so just keep that in mind.

Dr. Kanwal Raghav 22:55
And all these patients were divided into three groups, the highest group, or what is called as HER2 high or HER2 positive patients. And the reason why they’re called positive patients is because traditionally, they have been defined like that. They are patients who have HER2 amplification or HER2 level that is three plus or two plus, with amplification. Then comes this group of HER2 lows. And just keep that in mind, because we’ll come back to that in a bit– which express HER2 at a level of two plus or one plus. And basically this is just a gradation system of no HER2: zero and very high HER2 expression: three, so one and two plus is somewhere in between. So when they looked at these patients, you can see this is a standard colorectal cancer population. Almost all of them were RAS/BRAF wild type. Large majority were three plus. And 53 of these patients were these HER2 high patients or positive patients, and the other ones were HER2 low patients or negative patients. Actually, HER2 low is a better way of addressing them, rather than calling them negative. So clearly you can see right from the get go, with this waterfall plot that this is a very effective treatment in a highly refractory population. Response rates of about 40%, is somewhere where the middle would be, and we can see a majority of patients responding. But what’s really, really interesting is those that respond tend to respond for a very long period of time. This is time in months. So these patients are reaching like nine to 10 months of treatment and still having continued response. And the median PFS, as you can see, was clearly, about 6.9 months, despite the fact that only about 45% patients responded. So large majority didn’t respond, which means that the duration of response in patients who responded is actually even longer. What we didn’t see, unfortunately, was any activity in these HER2 low patients, so people who didn’t have amplification or three plus expression. And just keep that in mind, because this is an important subgroup that we need to discuss at some point of time.

Dr. Kanwal Raghav 25:30
And when you look at the treatment overall, it was actually pretty well tolerated. You can see that the grade three are the dark blues. Neutrophil count decrease was the main one, but not associated with febrile neutropenia in most cases. And diarrhea, which is one of the major problems with irinotecan, is very, very low.When it comes to grade three, like probably about 2 to 3%. And also remember, all these patients have had prior treatment with irinotecan. So just because they had irinotecan doesn’t mean this drug wouldn’t work, and for the right reasons, you’re just delivering extremely high dose of topoisomerase poison to the cancer cells.

Dr. Kanwal Raghav 26:17
So after that, a quick recap of emerging ADCs, and I’m going to go through these really quickly, because they are all in clinical trials. Just like HER2 this is another drug U3-1402, same payload, same characteristics as DS-8201 but the advantage here is that the target is HER3, which is actually more expressed in colorectal cancer than HER2. So HER2 over expression is seen in about 3 to 5% of RAS Wild Type colorectal cancers. But HER3 expression, a high HER3expression may be seen in as high as 40% of colorectal cancer population. So this is all about increasing the population that we can target, and thereby the HER3expression is actually a very, very attractive target. And go ahead..

Manju George 27:21
Can I interrupt you for a second? Do we have clinical trials for HER3 expression going on right now in the US?

Dr. Kanwal Raghav 27:31
Yes. So there is a U3-1402 study that we are participating in, which is open globally, which is accruing well. And just remember, in breast cancer and in lung cancer, this drug, just like DS-8201, in breast lung and gastric cancer, has shown activity. And this is also an example where you know that HER3 is not the driver of your cancer, because in breast cancer, in colon cancer, we have tried HER3 antibodies by themselves, and they have never worked. And the reason is because they’re not really driving your cancer. But ADCs don’t care about oncogenic mechanisms. All they care about is a target that they can bind to. So this trial is ongoing, and we hope that we will have good activity from this. But even if we don’t have good activity, or as good activity as HER2, the good news about these compounds are you can build on these compounds and add other drugs to them, because the expression of the target is more prevalent in colon cancer than, say, HER2, for example.

Dr. Kanwal Raghav 28:49
So again, these are pre clinical data showing good activity of U3-1402, in various kinds of models. And you can see that this is Patritumab, or the one in teal is actually the HER3 antibody, which, by itself, does nothing. But when you look at the U3-1402, you can see very good control of tumor and decrease in tumor volumes. And it’s a dose dependent treatment. This was data that was shown in breast cancer, and you can again see multiple responses in breast cancer population that was HER3 positive.

Dr. Kanwal Raghav 29:34
This is the current study that’s ongoing. Again, all advanced colorectal cancer patients. You need to have a biopsy to show you are HER3 expressing and again, very similar to Destiny CRC01 study. The HER3 high expressors and the HER3 low expressors, they all get treatment, and this is currently ongoing. The next drug is sacituzumab govitecan. This drug has received approval for triple negative breast cancer. It works against a protein called TROP2. TROP2 expression is seen in about 40 to 50% so again, a good marker, because the prevalence is more and you can see that a lot of activity in breast cancer. The payload here is not the same as trastuzumab deruxtecan or U3-1402. The payload here is SN- 38 which is the active molecule which comes from irinotecan. However, the drug antibody ratio in this drug is about two, two and a half. So again, not as high as we would want it to be. But this is another potential agent we could evaluate in the GI space. The problem that we have seen is when we evaluate this in the GI space, specifically colorectal population, you can see really one partial response, but mostly stable disease. And the reason why this could be happening is because of that low drug antibody ratio and the fact that most gastric, most colorectal cancer patients would have had prior exposure to irinotecan, which is not present in case of breast cancer. So that’s why you probably see this kind of [response]. So what we need here is a more potent molecule. So only one patient out of 29 had any partial response. So then that brings us to this drug, which is DS-1062. This drug is an antibody drug conjugate. TROP2 is the target, but the payload and the payload characteristics are the same as DS-8201, which is trastuzumab deruxtecan and U3-1402 against the HER3, which we talked about. They’re all under the same platform.

Dr. Kanwal Raghav 32:11
So this was done in metastatic, non small cell lung cancer, and you can see that there was some toxicities to these drugs, as there are mostly interstitial lung disease. Usually they’re less than 10% and with dose changes and early identification, you can manage them well. But you can again see in a refractory lung cancer population, an extremely effective drug, and we are in the process of starting some clinical trials with this drug. Right now, there are no clinical trials running for colorectal cancer population, per se, for DS-1062. Another drug is labetuzumab govitecan. Again, I apologize the names just keep on getting more and more complex. But basically, this is a CEACAM antibody drug conjugate. CEACAM is a common protein on colorectal cancer. It has seen almost a 90% colorectal cancer population. Again, very high drug antibody ratio, SN-38 is the payload, same as irinotecan , but fortunately, a higher drug antibody ratio. So that’s good, because you can imagine that if you can deliver a higher quantity of the drug, you’d be able to overcome prior resistance to irinotecan and you can see that in this population, we saw median PFS of 4.4 months, and you can see that there was limited toxicity, the same that you expect for most ADC’s.

Dr. Kanwal Raghav 33:51
So the landscape for ADCs relevant to CRC is large because of any HER2, CEACAM, AG-7, HER3, like we’ve already discussed before, but these are some other ADCs. You can see, majority of them are anti-tubulin. I’m a little less excited about anti-tubulin molecules in colorectal cancer, but that does not mean that we shouldn’t evaluate them, and then alkylators and topoisomerase inhibitors. So with that in mind, just remember that at some point of time, even if we have these ADCs that are working in colorectal cancer, will still come to the same point where we had been for the past 20-30 years. We develop a drug, we see these response rates, or two or three months overall survival benefits, and then we become complacent. And, and I feel that we should always not accept these sub optimal results as everything that we can accept and always try to improve upon it.

Dr. Kanwal Raghav 35:08
And that’s where these future directions come into the picture. So with HER2 we have always been able to target a very small proportion of colorectal cancer population, and that’s because the traditional HER2 drugs like trastuzumab, Pertuzumab, trastuzumab, lapatinib, trastuzumab derxtecan–it only is effective in patients where HER2 is the driver. So it only is effective when you see HER2 amplification, and it’s not effective when you see HER2 amplification in presence of a KRAS or NRAS mutation. And the reason is because the RAS is the driver then, not the HER2. Fortunately, ADCs can overcome that, and therefore we can have drugs like trastuzumab deruxtecan can potentially even benefit patients that have either RAS mutations and are HER2 amplified, for which there is no current evidence that any other drugs will work. And also, for this HER2 low category of tumors–so tumors which express HER2 but are still not dependent on HER2 for their growth. Like the HER2 2+ and 1+ in breast cancer. TDM-1 the older antibody drug conjugate did not work in that population. However, trastuzumab deruxtecan, at least in breast cancer, has already shown activity in HER2 low patients. And this is a very, very exciting opportunity, because if you can target the 2+ and 1+ , then you expand that population to almost 25 to 30% of all colorectal cancer. And again, you may not be able to to get the same degree of activity that you get in high expressors as single agents. But you definitely can do that with combinations.

Dr. Kanwal Raghav 37:11
And this is the classic slide where trastuzumab deruxtecan, and this is a 2+, 1+ tumor, where you should have no activity whatsoever. And you can see that these curves look very much similar to what was seen in the HER2 positive or HER2 high breast cancers with trastuzumab deruxtecan. And also with another ADC called Trastuzumab biocarbamazine, which is another ADC that has shown great activity in breast cancer. So this is really, really an exciting time, because you can increase that targetable population, and we need to move this forward in colorectal cancer. The problem with colorectal which is not the issue with breast cancer is in breast cancer, irinotecan is not the standard of care. And in colorectal you already have some exposure to irinotecan. So that’s why, in smaller studies, the HER2 low population is not showing as dramatic a benefit as we’ve seen, say in breast cancer. But there are things that we can do to make these drugs work better.

Dr. Kanwal Raghav 38:24
So what irinotecan or topoisomerase inhibitors or DXd does is it creates a DNA damage. In a normal person, that DNA damage can be repaired by a DNA damage repair mechanism, which is driven by ATR or ATM, and these genes. And we have ATR inhibitors and ATM inhibitors in the clinic. So the question is, why don’t we just give them with irinotecan? And the reason is that the systemic toxicities of both the drugs is so high that you are not able to deliver a high enough dose of either the topoisomerase inhibitor or the ATR inhibitor. So the advantage of the ADC is they increase your therapeutic window. They increase that possibility of giving that drug at that potency, because it minimizes systemic toxicities. So the rationale here is, if you damage the DNA by HER2 ADC, for example, or a HER3 ADC, or a TROP2 ADC, and then you bring in the ATR inhibitor, the cells will not have any mechanism to repair the damage that has been created by the topoisomerase inhibitor, and therefore the cells would undergo a mitotic catastrophe, or they will die because of so much DNA damage. And taking that into consideration, we have designed an NCI driven study of DS-8201, in combination with an ATR inhibitor, which should be active, hopefully by the next month.

Dr. Kanwal Raghav 40:13
This is another strategy in which in lung cancer, when you attach the ADCs to other HER2 drugs, they can increase the efficacy of the ADC by increasing the circulation of the receptor, which allows more and more drug to be delivered into the cells, thereby increasing the killing effect. And this is another strategy that can be explored for patients that either don’t benefit from HER2 ADCs to begin with, or are HER2 low to start with. There is some data about combining these HER2 ADCs, along with immunotherapy in which you can see that this is the HER3 antibody that we were talking about. It has effect. But when you combine with anti-PD1 it has even more effect, even though the anti-PD1 has no effect whatsoever in this population because it is MSS stable. So, I think with that, I’m going to pause and open this to questions. The last line that I always like to make at the end of these statements is especially for groups like COLONTOWN, who have done a lot of work in spreading the word and awareness in patients, and also for patients who suffer from these rare subsets or rare tumors, is as much as possible, please try to participate in clinical trials before going towards standard of care. Because as you can see, patients with gastric cancer and breast cancer and even lung cancer now have, unfettered access to these drugs because of the trials that have led to approvals whereas in colorectal, we are still yet to get a single approval for anti HER2 therapies. I mean, they’re part of NCCN guidelines, but NCCN guidelines are only as good as the provider that’s looking at them or that’s following that. So still a long way to go. But this is a great avenue and a great strategy that has come into our hands, and we should try to exploit this to the best of our ability to try to improve the outcomes for our patients with that, thank you for your patience, and happy to take any questions the group has.

Manju George 42:52
That is excellent. So in COLONTOWN, we have a HER2 clinical trial group. So we ask when patients join, we ask them if they know about their HER2 status, and then we put them in the group, and then we actually advertise– So the DESTINY 01 trial, MOUNTAINEER those kind of trials are sort of advertised there. And I mean, this data is so exciting that there are so many options available. And my question was about, I heard about interstitial lung diseases being a thing, a serious side effect for these. Is that some kind of reaction to the antibody part independent of the drugs?

Dr. Kanwal Raghav 43:34
Yeah, so the HER2 expression is seen in lung cells. And that’s why the interstitial lung disease is of concern. However for CRC01 study, we were one of the highest enrolling US sites. And we treated about 9 to 10 patients in that study, and only two of those had interstitial lung disease, but that also very mild, and it was easily reversed and did not create any problems for the patient. In one patient is actually managed by drug decrease in dose. So it is a very concerning side effect, because it can become potentially life threatening. In breast cancer, the interstitial lung disease was about 6 to 7% with the higher dose and with a lower dose, it was about, it is about less than 3%. Destiny CRC01 study was done at a higher dose. So now we are actually starting DESTINY CRC02 study, which is the second version of this study. This is a randomized study of DS-8201 different doses, just the way they did this in breast cancer. It’s a lower dose and the current dose in the CRC01 study. The reason why that trial is very critical, and I would strongly recommend people to participate on that trial, is three fold. Number one, if successful, that trial is built with registration intent and will lead to FDA approval. Number two, it allows KRAS mutant HER2 positive patients which are not benefited by any other means. And number three, it helps us to explore this lower dose, and therefore potentially have the ability to see whether 5.4 is almost as good as the 6.4 dose. And if that is true, then that means we would have dramatically decreased the side effects of the drug and allowing patients to be on the drug even for longer period of time.

Dr. Kanwal Raghav 46:09
So again, one of my fears always is, what happened with the BRAF study in colorectal cancer. We saw the early efficacy results. Everybody in the United States didn’t want to participate on that study anymore, and we all we saw that. You know, when we do randomization, that’s when we actually find out the true effect of that of that drug, right? Because if we would have abandoned the study at that time, we would have been giving everybody three drugs. And really, that’s not really required, it’s very clear. Also, it is very clear that the effects that we saw in early stages of that study did not pan out to be as robust in the later stages, which means there is still more work to do in that space. So even though trastuzumab deruxtecan is on the NCCN guidelines does not mean that they should be used as standard of care. I think they should be used as standard of care only in the absence of a clinical trial. And fortunately, we will have CRC02 study as an option of clinical trial for HER2 patients in the next few years.

Manju George 43:35
So another question is, so that is even though HER2 being is originally present in only 2 to 3% in RAS wild type patients, after EGFR inhibitor therapy there is acquired HER2 that’s I think about 8% or something. So do you think that those patients would benefit from these kind of ADC?

Dr. Kanwal Raghav 47:47
Yeah, So absolutely, I think as long as you have the HER2expression which is high, you should be able to benefit from HER2 ADC. Actually for a RAS wild type population, HER2 over expression may be seen in about 4 to 5% population of RAS wild type, if you sub select for BRAF wild type, it might be about six to 7% and yes, you’re right, there is some degree of up regulation of HER2 with anti EGFR. But again, like I said, our aim should not be just restricted to that, HER2 positive space. We need to try to get to a HER2 low population, and see how we can make these drugs effective. And that’s where trials like the NCI 10358, which is a study that’s shortly going to be open in combination with ATR inhibitor that will allow all levels oF HER2 colorectal cancer patients to enroll on it.

Manju George 48:52
Okay, okay. We are actually also having something, what we call a clinical trials center. We have started something– it’s like a learning place called the COLONTOWN University. So that’s one place we can highlight certain clinical trials. And I think these kind of ADC trials are something that is really important, and especially if you get enough data and if they could become standard of care, that would be amazing. So my other question would be about like you talked about TROP2 right? And then you were comparing HER3 , so each one of them is about 40%– are their expressions overlapping? Or are they distinct populations of CRC?

Dr. Kanwal Raghav 49:34
Yeah, so there are expressions that are overlapping. We haven’t done an overlap analysis to figure out what that population is, but I’m presuming that it would definitely be overlapping. Again, I feel that with ADC the good news is as long as your payloads are different, as long as you bring in a different strategy, you should be able to get effect, right? So, for example, one could envision somebody with HER3 getting an ADC, and then the ADC stops working, partly because the HER3 expression down regulates itself. And, that would be a great patient to go for a TROP2 strategy. And it can be done in multiple steps and series one after the other.

Manju George 50:22
Okay, okay, that’s kind of interesting. I think that’s the questions that I have. I’ll see if anybody else has any questions.

Manju George 50:31
Anyone has any questions? This is, this is a lot of information. Dr Raghav. I’m going to be posting this video in the group, and then I hope that when people watch them, and when they have questions, then I’ll email you, and then if you can get to the answers, that would be great. The other thing would be like when you have the other trials, the newer version of the DESTINY 01 or these other trials that you were talking about, if you send me a schema, like, just a figure with that, and then some contact information, I’ll be happy to post in COLONTOWN, because we have a lot of discussion about trials, and especially with the HER3 ones and all — it’s not something that comes up in the different tests, the Foundation One or something, because HER3 is not something that people are looking at. So those patients who are out of options, these would be a great trial to try

Dr. Kanwal Raghav 51:32
Sure I can send you the schema for some of the trials that are exciting in this particular space.

Manju George 51:38
Okay, okay, I think doesn’t look like people have any other questions. So after I post this, and I’ll collect questions, and then I’ll email you. So thank you so much for your time.

Dr. Kanwal Raghav 51:49
Thank you, everyone. Have a nice day. Take care.

Manju George 51:53
You too. Thank you. Bye.