NeoGenomics, Inc. (NEO) Earnings Call Transcript & Summary

Good morning, and thank you for joining us for this morning's Breast Cancer Tumor Board. We are so glad that you are joining us today. [Operator Instructions] As always, shared cases are what makes this program successful and we encourage submission. Should you have a case that you would like to present at one of our tumor boards, please send an e-mail to [email protected]. The programming today is brought to you by the Medical Affairs department at NeoGenomics whose aim is to foster education and promote the understanding of cancer within the global scientific community at large through programs that enrich medical and scientific knowledge of cancer diagnostics that point the way to advancing patient care. As part of our commitment to education, we would like to invite you to join us for our Diagnostic Symposium next month hosted by NeoGenomics' Dr. Lyle and featuring Dr. Razelle Kurzrock from the WIN Consortium. Registration is required, a RSVP link will be provided in the comments section shortly. In addition to our breast tumor boards, we also have a lung tumor board series. We invite you to join us for that as well. The link to register will be provided in the comments section. Our host today is Dr. Fernando López-Díaz, Principal Scientist in Research and Development at NeoGenomics Laboratories. Dr. López-Díaz, welcome.

Good morning, [ Susan ]. Good morning, everybody.

And joining us today to moderate today's tumor board is Dr. Jayanthi Srinivasiah from Georgia Cancer Specialists. Dr. Jay as she is affectionately known to her clients. Dr. Jay is board-certified in medical oncology and hematology with over 2 decades of experience. She has been honored numerous times as a doctor in Atlanta Magazine and other publications. She is actively involved in the field of research, hereditary cancers and genetics as well as breast cancer. She participates in multiple hospital leadership committees and serves as a principal investigator for clinical trials. Dr. Jay, thank you so much. We are so happy to have you here with us today.

Thank you for inviting me, and I'm excited about this conference today.

We are very excited. We have 3 wonderful cases to discuss. So I am going to get us started with our first case. And Dr. Jay, I will turn it over to you.

Thank you. So okay. So before I get started with case 1, we've chosen 3 cases to present today. And of course, we are always welcoming anybody's input who's on the line to bring up any case that may be similar or questions that may be related. But we decided to choose 3 patients who are HER2 -- with breast cancer that were HER2 expressers because of; one, the new treatments that are becoming available for HER2-positive breast cancer; and also to see how genomics ties in to the immunohistochemical markers in HER2-positive disease and see where we are heading in the future. And our patients are having so many options of therapy, and we're keeping them alive and going for long periods of time because of the research that's going on in this area. So to present the first case, this is -- this lady in 2011 was 30-year-old, now she is 42-year-old. And you can see how well she has done considering what we were dealing with. At the beginning in 2011, she was diagnosed with breast cancer of the left breast and received neoadjuvant chemotherapy. Initially was ER positive, node positive, but then we had the pathology specimen, she ended up being HER2 positive. Can you advance the slide? Okay. Now I can. Okay. So she ended up being HER2 positive. [ Susan ], I can't advance the slides for some reason.

Do you want me to adjust...

Yes. Can you just go to the next. Oh, no, the previous. Now it did. Okay. So that's good, leave it there. So she ended up being HER2-positive with the pathology specimen, got anti-HER2 therapy, but since then has had at least 3 recurrences and has had a therapy with Herceptin, Perjeta, taxane, ended up getting KADCYLA because we didn't have any other options at that time and now has growing metastatic disease in the liver and was started on the antibody drug conjugate in HER2. And so we thought we would discuss her genomic testing, which then ended up showing that she was -- had PALB2 mutation. She has ER positivity and HER2 positivity, so a lot of different targets that we have available and how do we incorporate all of this. And I'll have Dr. López-Díaz comment on her genomics for a minute, and then I will tell you what are the different options. Can you move forward to the next slide, please? So these are all the various therapies that she has had over the years. Next slide. And since -- we'll stop here. Since she has had repeat biopsies of the liver, which have confirmed HER2 positivity, we have her on the ENHERTU, which is the trastuzumab deruxtecan. And we are awaiting results of her scans as to how she would respond. So Dr. López-Díaz, do you want to make any comments on her genomics and then we will move on with the various options that she might have?

Yes. So this patient, it has been tested. I know it's been referred for BRCA testing already, which given the age of the patient makes complete sense. I don't have the result of that. But when it was submitted to our laboratory, and I think it was BRCA negative, to be honest. But when it was tested in the laboratory for genomic alteration -- somatic genomic alterations, it was detected a PALB2 truncating -- or frameshift truncating variant, position Serine 254. And that's a loss of function, alteration. And it was detected with an allelic frequency that is coherent with a potential germline alteration. We cannot -- this was performed using a test that has -- test for somatic versus germline alterations, and we cannot comment. This has not been performed in our laboratory. We cannot say whether this was confirmed or not to be the germline alteration, to be honest, but that's what we see here. An interesting fact about this alteration is that typically PALB2, which is a homologous recombination related gene that interacts with the BRCA genes in order to repair the effect and during replication. One of the common features when these type of alterations appear is that there are lots of function events and lots of heterozygosity at the same time where you lose one allele as a germline, and then there is an additional alteration, typically, is loss of one gene, basically copy number alteration -- variations and then truncated mutations. Those are the most frequent findings for PALB2 alterations. And PALB2 refers as a BRCAness conferring alteration, so yes, that's a...

Yes. So we had -- actually, I presented a case maybe a year or 2 ago. We were discussing about the options of PARP inhibition in the HRD pathway genetic abnormalities. But unfortunately, PALB2 has still not been approved for PARP inhibition yet, and I've been struggling to get her treatment with the PARP inhibitor. But we do know, however, that any of these HRD genes, platinum would be a good option. And so she would be treated with platinum as a next option when it's -- when she progresses. But she also has very high HER2 expression and she has multiple therapies available. And I just wanted to bring up with you all where we are with the HER2-positive breast cancer. We know that pertuzumab, T-DM1, she's had both of those. There are many tyrosine kinase inhibitors that are showing promise, especially with CNS disease, tucatinib, neratinib and pyrotinib. And of course, the -- she's already on this trastuzumab deruxtecan. And that is hoping that, that will also prevent her with developing brain mets, but she does not currently have brain mets. We've done an MRI of the brain. There is another drug antibody conjugate which is SYD985, which I will present to you later. And the Fc-engineered antibodies are also approved now and she has options of that as well. So lots of options for her future treatment, platinum-based therapies. Hopefully, if we can get her through for another year or 2, the PARP inhibition will be approved for PALB2. But PARP inhibition has been approved for pancreatic cancers with PALB2 mutation because there have been studies with that. For breast cancer, however, that's still in the clinical trial setting. I haven't sent her for those clinical trials yet because there are so many other options available. But she's on year 12 of her treatment and still performance status of 0 and doing well. So I'm open to any questions. Are there any questions, [ Susan ], on this case? I thought it would be fascinating things to discuss...

I think we might have a question that has come in through the Q&A. What about testing for HRD score? There are FDA-approved PARP inhibitors for HRD-positive status.

Yes. Right, which we are doing -- that is a good question because in the genomic analysis, we do, do HRD scores in addition that I've been doing for all my breast cancer patients. Again, we are having difficulty getting approval for PARP inhibition for breast cancer. For ovarian cancer with HRD abnormality, I'm getting approvals. For prostate cancer, I've been getting approvals. For breast, we have not yet, but hoping that very soon, we'll be able to get that. Again, for this lady, I'm sure before we exhaust currently available therapies, we'll be able to get it approved. But very good question. And I've been including that with my genomics on a regular basis. Do you want to comment on that Dr. López-Díaz, HRD with the genomics.

Yes, sure, definitely. We know that when we think on the biology of the tumor, these PALB2 alterations would be 100% consistent with an HR -- with homologous recombination deficiencies overall because of the relevance of PALB2 in the homologous recombination repair. But again, it's more about the approvals and finding the targets, being able to have a drug that hits the target and then ultimately in clinical practice, sometimes what Dr. Jay refers getting those therapies approved is what probably is the last but not that simple step. An important comment on this is what you commented, Dr. Jay, the possibility of putting these patient in platinum.

Correct.

Here, we see also that the genomic profiling can -- it's been assumed that every time you perform a genomic test on a patient is that yet to provide a targeted therapy. And in the case of HRD-related genes like PALB2 or even the BRCA gene, there is an -- there are very good therapies that are not necessarily targeted in the sense we understand them or we know them, but are highly successful and efficient because of the mechanism of action that they have. And platinums are such type of mechanisms because of the type of DNA damage that they produce during replication that involves the homologous recombination repair machinery that in this case would be effective.

Yes. I think there was somebody that was going to comment. [ Susan ], do you have that? It was a pathologist.

Yes, hold on 1 second. Okay.

This is Nhu Ngo. I'm the Director of Molecular Path at NeoGenomics. This is a great talk. Actually, I spent 15 years in practice, and breast cancer was one of my major areas of focus. So I just wanted to comment again on the HRD score. That was actually my question is, yes, totally understood that having the PALB2 mutation may predict response to platinum and/or PARP inhibitors. But the HRD score is a more direct measure of predicting response to platinum or PARP inhibitors than just having the mutation. And understood that in both situations, whether you have the -- just a mutation or an actual HRD positive status, it's still off-label for breast, for PARP inhibitors. But I believe that the HRD score is measuring the consequence of...

Yes, good point. So...

Absolutely.

I agree totally. So I think getting that is critical in our patients. Irrespective of whether she had the PALB2 or not, I think that actually has helped us. So I'm hoping that in the future, the clinical trials that we're going to see will not really look at whether they are BRCA1, BRCA2, CHEK2, PALB2, but they'll be looking at HRD status is my response.

I completely agree with you because, again, that's the real predictor of response. And there are cases where HRD score is positive, but we don't see a mutation in any of the HRD genes. Sometimes that's due to actually copy number variants or methylation of BRCA, so you wouldn't pick up a mutation.

Okay. Okay. Thank you. Thank you for that comment.

Thank you.

So if there are no other questions for case 1, should we move to case 2, Susan, I think.

Yes. Let's move on to case number 2.

Okay. Yes. Before that, I had just one comment. Can you go back to the previous slide.

Absolutely. Yes.

Yes, one before that, yes. So this slide is just a cartoon to show that where we are heading with our anti-HER2 therapies. Again, we talked about the novel drug antibody conjugates, the TKIs. There are some bispecific antibodies that are in clinical trials. Then we're trying to incorporate immunotherapies and vaccines, and that's where also, I think the genomics kind of comes into play as well to get -- to look at combining 2 or 3 of these options. And so I just wanted you to remember this cartoon. Later on, we'll discuss more details about clinical trials in HER2-positive breast cancer. Next slide -- previous, yes. So again, this is just to remind us that it's not enough to just do the IHC for HER2 and get the positivity and treat patients. In a given tumor cell, you may have others like PI3K abnormalities, checkpoint abnormalities, CD4/6 abnormality. And so the target here doesn't have to be just the HER2, it could be the others as well. And just to kind of say, in a given patient, we need to look at all these targets and how important genomics would be in terms of adding to the IHC markers that we generally do for breast cancer. Even if they are HER2 positive, yes, we have one target. But getting all the other targets may be equally important to choose your strategy and your algorithm of treatment. So just exciting times for us with breast cancer. So now I think we can move on to case #2, Dr. López-Díaz.

Yes, sure. Well, we move, I think that just a slight comment to that is that for instance, we are seeing nowadays more studies are coming. For instance, addressing specifically resistance to trastuzumab and other HER2-directed therapies where a variety of genes have been found altered as the patients progress and also some alterations, such as those in CDKN2A and CDK12, ERBB2 as well, so HER2 itself, and other genes like MECOM, which are much less now, but they predict prognosis and they can guide actually therapy selection, and they might be preexistent before the therapy is administered and they are predictors of poor response to trastuzumab, for instance. Okay. So let's go to the next patient. This patient is at present a 43 years old female, was diagnosed, I believe, at age 41 from our notes. And this patient is present with Stage IIIA infiltrating ductal carcinoma. We -- let's go to -- I think that the important point on the note here, yes, that one. This patient was basically on a medication after a year. She developed shoulder pain and an MRI was done and then an irregular hypoechoic mass at the periphery basis show recurrent disease. The ultrasound-guided biopsy was consistent with invasive ductal carcinoma grade 2. Please, next slide. So the patient is triple positive, so HER2, PR and ER positive. Next. And when it was -- the most recent testing, genomic testing had revealed an alteration on PIK3CA, alteration E542K, one of the common alterations. Also, it's shown amplification positive by FISH, and it shows MYC amplification. The patient is microsatellite stable, and its tumor mutation burden was found intermediate with 7.4 mutations per megabase. In terms of other immuno-oncology-related biomarkers, PD-L1 was tested with companion diagnosis for Tecentriq, the SP142 antibody and was found no expression. And an additional IHC was performed with a Pan-TRK antibody and no expression by immunohistochemistry was found on that. No abnormalities were detected in BRAF, BRCA1 or 2, EGFR, estrogen receptor 1, KIT, KRAS, NRAS or PDGFR. So I think there was one more thing about these patients. No. Next slide. Okay. Dr. Jay. I think that -- here, the allelic frequency, I forgot to mention, the allelic frequency of PIK3CA is about 27%. Now yes, Dr. Jay it's your case.

Okay. So basically, very exciting to see the genomics here. When you see this -- the slide that I showed you, HER2 may not always be the target or could be a combined target of HER2 and PIK3CA. So for this particular patient, yes, we will use anti-HER2 therapy, but can be used also PIK3CA inhibitors. So now there are clinical trials opening, I'll show you the very last slide when I do my last presentation that there are clinical trials looking at the combination of PIK3CA inhibitors with anti-HER2 therapy, and this case would be very good for that. The second is also there was some increase in tumor mutation burden. So there are some clinical trials looking at adding atezo with anti-HER2 therapy. We are part of one of those clinical trials. So that is also exciting. So there are maybe more targets than just the HER2 target. So that is what I wanted to bring up with this case. And next slide. So I think we have -- again, I -- yes, keeping good, yes. So again, the same slide, I put all the 3 same slides just for us to think about what are the various options of therapy. Next slide. Just to tell you that these all these 4 interact with each other. And in this particular case, next slide, we would have more than just the anti-HER2 target, in this case, the PIK3CA. And apelisib is being -- alpelisib is being used in combination with anti-HER2 therapy in this clinical trial that we have open. There's a number here, but there's also a list of clinical trials at the end for people in the audience that may want to look at their patients and consider trials. Next slide. So we can -- this ends case 2. Any questions on case 2, Susan, anything else? Any other comments, Dr. López-Díaz.

Actually, I found one in -- again, I think...

I think that was asking from before.

Yes, that was from before, okay.

[Operator Instructions] Since we don't have any questions currently right now, let's move -- go ahead.

Sorry. No, I think that we have this situation where we've seen several patients that are HER2 positive and some of them they can with amplification of MYC. And I think we've discussed -- can we discuss about what the role of MYC amplification is in breast cancer? And one interesting fact about this is that MYC is typically upregulated by estrogen in ER-positive breast cancer cells. And basically, it plays a critical role in estrogen-induced breast cancer proliferation. So MYC protein stabilized in response to estrogen. And this is probably one of the paths are where they intersect. Interestingly enough, there are some clinical trials for anti-MYC therapies. There is specifically currently recruiting Phase I/II clinical trial starting basically the safety and efficacy of MYC inhibitor compound.

Interesting. Yes. Just fascinating how far we've come with all these targets. And yes, so when I look at a patient, I always start thinking, one, how do I strategize various therapies? And then there are so many options available. The one thing that you would have to -- I look at where the -- say, for example, on a PET scan or on a CT, you have growth of one area, the other areas are stable. Many times, I tried to biopsy the area that is growing to see if that expresses any particular target that we might focus on. So that may be one way, and sending that for genomic analysis. That's how I've done with this lady and she's kind of moved on to year #12. So I'm hoping we can continue to do that with my first case. And similarly, with this case, I hope they are doing that. So that can segue into our next case, which is also very fascinating. Is that good -- should we move on to case 3?

Yes, yes. Yes, we should move into the next case, I think.

Okay. So case #3 is a 50-year-old. Again, she was also diagnosed almost -- can you go to the next slide? Okay. It's been almost 8, 10 years. Again, very similar situation, received neoadjuvant therapy, had -- for HER2-positive breast cancer and had recurrence in the left chest wall and subsequently has developed mediastinal adenopathy and liver metastases and bone metastases. And most recently, she's had multiple lines of therapy as well. And so we decided to do genomic testing to see if there were other targets other than the HER2. And so this is her genomic testing. Can you talk about the limited abnormalities and what you would suggest on this?

Yes. Well, this patient presented basically 2 alterations, 2 somatic alterations in p53, one in a rather -- in the N terminus region, it's outside of the typical alterations that we will see for p53 in the DNA binding domain. That's where most of the loss of function alterations in p53 occur when there are nuisance like this one and another 1 in the actual DNA binding domain mutation I95Y. But both of them at a very low allelic frequency, which suggests that they are subclonal. So indeed, in this case, it is, in a way, interesting that, that would be the only alteration detected. And it's probably surprising to most of us that are used to see genomic testing because p53 in breast cancer has been definitely, and it is an alteration commonly seen. But seeing only p53 alterations, which, by the way, are typically detected after tumors are larger than 2 centimeters long, that's basically coming out of long years of research. So it's not the initial mutation that has been detected in breast tumors. But being the only one, it's a little bit surprising. So it might be interesting to get a current profiling of a new biopsy that the patient has developed mets at this point.

Yes. So my thought process was the biopsy that was sent off for genomic testing initially was the same left chest wall mass because it was easily accessible that kind of grew bigger. So like you said, maybe that was the area that was increasing in size, and we did that. So now she has liver mets. I'm thinking about biopsying the liver and sending it off for genomic profiling. But with her being HER2 positive, and now we had thought about putting her on a clinical trial with the same in ENHERTU plus tucatinib trial, which is a TKI inhibitor. So we did an MRI of the brain to see if she's eligible for the trial, and she had multiple tiny lesions in the brain that had come up since the previous CAT. So that kind of tells us that -- we know that the HER2-positive disease has increased propensity to travel to the brain, especially within the first 3 years of adjuvant therapy. We see that. But again, there are many trials looking at metastatic disease even with brain metastases and showing response to systemic therapy. And I'll show you some of those slides after we finish discussing this case. So with the antibody drug conjugate therapies. So she has been started on ENHERTU and tucatinib trial, and we're still -- we're -- she's just on cycle one. And we have biopsied and sent off more genomic testing, and that's still pending at this time. And once we get that, we can re-present her case next time to give you details of her expression -- genomic expression. But just very fascinating situation. Any questions on this case from any of the participants. Please ask questions so, then we can all learn from them. No, Susan?

Okay. One quick comment. It will be interesting if in those, the patient shows any alteration. One of the most common pathways that presents altered is the Rb-CDK4/6 pathway, not necessarily with mutations in CDK4 and 6, but mutations in CDKN2A or RB themselves. And it's interesting that palbociclib, for instance, has demonstrated intracranial activity in breast cancer patients. So it will be interesting to see if that would eventually show up. I don't recall exactly what time this test was performed in the past and in which lab? I know it wasn't in our laboratory, but I'm hoping that a new biopsy would reveal more genomic finding specifically as she has progression...

So the repeat biopsy will be sent to a different lab just to get a different perspective. And it will be -- it is done from the liver. So we're waiting for that. So hopefully, we'll get more alterations that we may have other targets. So I just saw a question from somebody that said when would we recommend genomic testing in a patient with HER2-positive disease or in general breast cancer? And I can tell you, from a clinician's perspective, what I've been doing and Dr. López-Díaz, please chime in and tell us what you think we should consider. So what I've done is for triple-negative breast cancer, since there were very limited therapies available and there was also data with checkpoint inhibitors, I was doing them at the very beginning of diagnosis. But now I'm learning that it's these other targets are there for any breast cancer. I mean, whether it's HER2-positive, HER2-negative, ER-positive, I think we need to do these genomics at the very beginning. And it's not sufficient to just do it at the beginning. And I remember you saying how things can change with therapies that we have -- we give and the alteration in genomics. And it almost requires a serial testing and how often should we test and how -- and what do we test and what type of tissue, all those things would -- I don't think we have answers to everything, but just we're learning with every case and as time goes on and new trials come up, but I'd like your comments on that.

I'd like to make a comment -- well, go ahead. Go ahead. I'll comment after you finish.

Well, I think that -- excuse me. Well, basically, knowing -- knowledge gives you power and knowing your patient's tumor genomic profile, and for that matter, any biomarker enabling profiling would be important. And of course, I know that there will be limitations about what you can do regarding coverage and insurances, et cetera. But one cannot negate the fact that knowing upfront what the genomic alterations in the tumor can be. And I was mentioning HER2-positive patients might be resistant to trastuzumab, a very common drug. And sometimes, this is related to our -- due to CDK12 amplification, ERBB2 amplification per se, MYC and POLE alterations that might also open avenues for a different path of intervention or to help you sequencing and having a plan for sequencing your therapy without having to wait especially when the patients progress. I'm not the one that would necessarily indicate when the testing should be done. But obviously, the sooner you can get it moved is the most helpful, and we can see more benefit in Stage 2a, 2b or Stage 3 diagnosis than it will be maybe in stage 1 stage, but then it's the physician's choice, of course, and how this can be accomplished in each given patient. And Dr. Ngo has a comment to make.

Yes. I think there were 2 comments. So we'll -- Susan, can you coordinate that please, yes.

That's actually me who wanted to make the comment. So -- yes. So in breast cancer, as you say, it seems like you've had wonderful success having therapies in -- serially planning out your therapy so that these patients are living for years. And so I would -- you probably do use liquid biopsies, but that is a phenomenal way to serially track patients as they are on therapy to see if they are responding or especially when they stop responding to see if there are resistance mutations and clones that arise. And so you don't always have to go after the tissue. So right now, liquid biopsies are being used in multiple ways. So if the patient goes for surgery, you can use them post op to see if there's minimal residual disease after surgery that has curative intent. But really, if a patient is -- has already been on therapy and you're going to continue therapy for years, serial liquid biopsies, I found is a wonderful way to...

So it looks like, yes, we're all heading that way because of the ease with which we can do it, the ability to interpret equally well and to do it more often. In terms of the cost, is there a difference between tissue versus liquid?

Yes, typically not. And in fact, liquid biopsies because we're not doing FFPE tissue, the extraction process is actually easier. So your turnaround time is usually faster, and the gene panels tend to be slightly smaller than the big multi-hundred gene panels that tissue -- for tissue because with liquid biopsies, we do have the sequence at higher depths. And so ultimately, though, I believe that liquid biopsies because they are meant to be used serially are not in a -- don't cost more than the other NGS assays. It's essentially a similar technology. Having said that, yes, it is, reimbursement is always an issue, I think. But the same goes with whether or not you're trying to do NGS on tissue or liquid. You still have the same read...

I think primarily -- yes...

One major advantage -- yes. One major advantage of the liquid biopsies is even if you can't see the metastatic sites, you may be able to detect all the different clones. If you biopsy tissue, sometimes if you have more than one metastatic focus, the genomics are different in the metastatic foci from each other even. But the liquid biopsy enables you to see the entire picture because all the tumors typically shed.

You kind of can look at it as a sum of all this.

Exactly. So that is a major advantage. And lung cancer patients are getting liquid biopsies much more routinely, I think, than in other tumor types but I think practice is...

I think we need to look at more of that in breast cancer as well.

Absolutely.

And this is a learning process where I think we're figuring out. I think this step is to say genomics help in general, which is what we're trying to drive home. With these 3 cases, yes, genomics helped. And then we say, how would we obtain that and how often do we obtain it? So those are all the various things we have to still learn over time.

Yes. An additional point is that it's a very -- it's important -- all right. It's important to point out that combining the tissue profiling to have a baseline of the molecular alterations of a tumor often helps because the value of the liquid biopsies is that you can see all the different clones at once. You might not see what -- you might not distinguish what mutation is coming from the most indolent alterations versus the most aggressive alterations. And so there is a trade-off, and I think that in -- overall, the message is that all of those different tests, they -- each of them provide a unique advantage that needs to be used as possible. And that's probably where we're going to be heading in the very near future. And we know that for lung cancer that has been much further advanced, even the liquid biopsy assays are often a little bit more selective to alterations that are most expected on lung cancer, maybe for that exact reason in how they were historically being developed and brought up to the clinical space. And we need to remember that there are certain tumor types like breast cancer, which rely much more in DNA repair and homologous recombination genes. And sometimes, not all these genes are included in existing tests that interrogate the cell-free DNA.

Okay. Good point. Thank you so much. So were there any other questions on case #3 or should we move?

I don't think so. I know you took some time to prepare a lot of wonderful slides, so I would love to give you that opportunity.

Yes. So basically, this is the first slide that I had just showing -- I went through this in terms of what are the different options for HER2-positive breast cancer. Next slide. So this is the CLEOPATRA trial where we looked at 1,436 patients. We looked at pertuzumab, trastuzumab and docetaxel versus placebo that means in the place of pertuzumab, suggesting that the combination of the 3 drugs had a better progression-free survival and overall survival. So this has become our standard first-line metastatic treatment for metastatic HER2-positive breast cancer. Next slide. So this, again, then this led to a trial, the HER2CLIMB trial, which looked at, if you have progression of disease on that combination, what would you do? So if patients had progressed on trastuzumab, pertuzumab and possibly even to T-DM1, we looked at the HER2CLIMB where the overall survival, the -- even the disease progression in the brain had improved. Next slide. So this is looking at the HER2CLIMB looked at a combination of TKI and trastuzumab and capecitabine versus without a TKI. In the place of the TKI, there was a placebo, trastuzumab and capecitabine, there was a difference in the progression-free survival and overall survival and brain metastases. So this is now becoming available as a second-line therapy for patients who have had previous trastuzumab, taxane and pertuzumab. And if they failed and also if they had brain mets, they could go on this combination. Next slide. Keep going further. Next slide. So the AEs that are important to remember, many of them were due to the TKI, and it was liver toxicity looking at -- the liver function test is critical. There was increase in bilirubin that was also seen. It could have been due to other medications as well. But that is something to pay attention to when the patients are given this combination. Next slide. So there are 3 oral TKIs now available for HER2-positive breast cancer, the neratinib, pyrotinib and poziotinib. So many options, again, just telling us that combinations of these with trastuzumab, with lapatinib combinations are all being looked at and will be available for us to use if -- especially if toxicity doesn't permit one or the other, you could -- you have 3 options moving forward in the future. Next slide. Now we come to the drug antibody conjugates. There are 2 that are available. One is the -- one that I already talked about, the trastuzumab deruxtecan, which is basically ENHERTU and how we look at many attributes of these ADCs. You look at the payload, what is the drug that's used. It is topoisomerase inhibitor in ENHERTU, whereas in T-DM1, which is KADCYLA, it is an antimicrotubule agent, which is emtansine. And if you look at the drug antibody ratio, it's 8:1 for ENHERTU as opposed to 3.5:1. But more than anything, there's a tumor-selective cleavage linker with the ENHERTU as opposed to the KADCYLA, and there is also a -- because of this, there's a bystander tumor effect seen with the ENHERTU. So that's one of the things that -- to remember the differences between the two. Both drugs will have a place in treatment of anti-HER2 therapy, but just to show you the differences. And the DESTINY trial, next slide, one of the toxicities that need to be looked at with these drugs are the ILD or pneumonitis. But once we've figured out how to monitor them, look at the X-rays, look at asymptomatic patients versus symptomatic patients and how to redose them if they -- the symptoms have resolved within 28 days and also making a dose level reduction if it is still persistent. All of those have been figured out, and this slide will speak for itself for people who are using the drug. And it's very important to pay attention to the ILD/pneumonitis with this drug. Next slide. So this, again, gives you the grading of the ILD and how many patients had it. Next slide. So this is the DESTINY trial, looking at randomizing patients to the T-DXd and T-DM1 where patients had previously been treated with trastuzumab and taxane in the metastatic setting. Next slide. So again, showing that there was a benefit in progression-free survival, overall survival and decrease in brain metastases for all of them, but you look at the median progression-free survival for the T-DXd, which was 25 months as opposed to 7.5 -- 7.2 months for the T-DM1. So again showing benefit for this particular drug ENHERTU, which is the T-DXd. Next slide. So this is the DESTINY trial, again, looking -- showing the benefit with brain mets. So this is really fascinating that my patient is on this, and I'm hoping that her brain metastases will resolve. In the past, we would have actually given radiation therapy to the brain and then started them on anti-HER2 therapy. But now that she's not symptomatic with the brain mets, we decided to just treat her with systemic therapy. Next slide. So the next slide, this is again showing the same thing. Keep going, keep going. This again showing the ILD. Next slide. So this is the other drug antibody conjugate that's available, which is SYD985. And now the clinical trial is ongoing, randomizing 2:1 to this investigational drug versus patient -- physician's choice of treatment and the different treatments are listed below. If doctors are interested in this clinical trial, it's available and accruing. Next slide. Again, some of the published data on this early trial, early published data, again, showing ILD is one of the toxicities that needs to be monitored. Next slide. So again, we're -- with anti-HER2 therapy, we have lots of other options available. And margetuximab is now available for treatment approved by the FDA. It's an Fc engineering, alters Fc receptor affinities and activates the immune system. So that's how this drug works. It has the same efficacy and affinity to the HER2 receptor. And so there are certain class of the patients that responded well. And next slide, I'll show you that. So again, they're showing benefit with this drug against trastuzumab plus chemotherapy, some progression-free survival benefit. Next slide. But when they took these patients and studied them further, the advantage was seen more in homozygotes with the CD16A homozygotes had a better response to this margetuximab. So again, genomic profiling and looking for these homozygotes may be -- may lead us into a path that's different from our standard algorithm. Next slide. So again, this trial is open and accruing, looking at margetuximab with paclitaxel versus THP and paclitaxel with trastuzumab and pertuzumab on the other -- which is a standard treatment. So the trial is accruing and again, patients may be eligible, but this is in the neoadjuvant setting. And in the metastatic setting, this drug has already been approved. Next slide. So again, just to emphasize to you all the various things that are available for anti-HER2 therapy and just exciting times for this disease. And again, genomic profiling on a regular basis, IHC profiling on a regular basis when patients develop resistance or metastatic disease, as there are many options available for therapy. Next slide. Next slide. So I want to go to the last slide, which -- this, again, driving home that there can be more targets than just the HER2, which occurred in every one of our patients, as you could tell. And next slide. This, I wanted to bring this up and I want Dr. López-Díaz's comment because we are now seeing that this drug antibody conjugate is helpful in patients with HER2 low disease. Can you make a comment on that, Dr. López-Díaz?

Well, one important thing about HER2 overexpressers is that we understand that, of course, whenever there is an increased expression of HER2, it will lead to -- sorry, it will lead to enhanced activity, but another possibility to obtain HER2 exacerbated activities through actually ERBB2, the gene that's cause for HER2 mutation, that keep the protein in a constitutively active manner. And indeed, there are mutations in exon 18 of ERBB2 that have been shown to be gain-of-function mutations. And this is one of the main possible explanations for the low -- sorry, the high efficacy on HER2 low breast cancer patients.

Okay. Yes. So this clinical trials are opening with the low HER2 expressers. And just stay tuned and please participate in these trials. Next slide.

And while you move...

I have a list of -- go ahead, yes.

No, just a quick comment. You were commenting on these novel therapies, and you were saying, well, it's not just all about HER2. One important therapies -- one important point about HER2 is that as an EGFR family of signaling, it has downstream the PIK3CA pathway. So if you have PIK3CA activating mutations, that's downstream of the HER2 pathway anyway, and it would negate the response to HER2 therapies. So one has to be cognizant of these type of molecular pathways or cancer pathways at the time of selecting. And it points out to the importance of having more knowledge about what is the genomic profile of the patient because it can help you recognize these type of potential negating mutations.

Yes. That is where I think combined therapies may be beneficial, and clinical trials targeting both abnormalities would be necessary. So this is a list of clinical trials that are currently very active in HER2-positive disease. And I'm not going to go through each of them, but they're looking at different parts of the disease. And I think we're almost at 1:00, so I don't want to take people's time. But basically, if you can read through the different trials and just excited that we are moving forward and looking at various targets in HER2-positive breast cancer and looking at various combinations. And hopefully, the patients that we presented will be eligible for some of these and we can re-present them years from now. That's my hope with all these new things that are happening. So I am open to any questions or comments. Susan, do you want to...

I think we -- yes, we are actually at the top of the hour. So I don't want to take any one more time from anyone. I do want to say thank you very much, Dr. Jay, Dr. Lopez Diaz. This was a wonderful discussion. Thank you to everyone who has joined us today. We do hope you will join us. Our next breast session will be on June 8. We also have a Lung Session on May 4, and our Diagnostic Symposium on May 10. RSVP is required for the Diagnostic Symposium, and there is a link in the chat, should you want to join us. And with that, I'm going to say thank you very much, and have a wonderful rest of your day. Goodbye, everyone.

Thank you.

Thank you, everybody. Thank you, Dr. Jay.