NeoGenomics, Inc. (NEO) Earnings Call Transcript

Good morning, and thank you for joining us this morning for the NeoGenomics Molecular Tumor Board. We are so excited that you are with us today. A few housekeeping items before we get started. Questions are welcome and encouraged. Should you have any questions for our presenters, please submit via the Q&A on the bottom tool bar. As always, shared cases are what makes this program successful, and we encourage the mission. Should you have a case that you would like to present at one of our tumor boards, please send an e-mail to tumorboards@neogenomics.com. 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. In addition to our breast tumor board series, we also have a lung tumor board series. We welcome and invite you to join us for those as well. On your screen, you will see a QR code for the lung series. You can take a picture with your phone, and it will bring you to a link. Additionally, a link will be provided in the chat section shortly. Our host today is Dr. Fernando López-Díaz, the Director of Clinical Science at NeoGenomics Laboratories. Dr. López-Díaz, welcome.

Welcome, Susan, and welcome, everybody.

Thank you. and joining us on our panel today is Dr. Nhu Ngo, the Director of Molecular Pathology at NeoGenomics Laboratories. Dr. Nhu is an oncologic and molecular pathologist and the Director of Molecular Pathology. She is board certified in anatomic and clinical pathology as well as molecular genetic pathology. She has been practicing for 20 years, including 15 years in hospital-based settings. Her interests are in molecular oncology, including targeted therapies, liquid biopsies and evolving biomarkers. Dr. Nhu, welcome, we are so glad that you are with us today.

Good morning. Thank you.

And our moderator today is Dr. Hatim Husain. Dr. Husain is a medical oncologist and Associate Professor of Medicine at UC San Diego's Moores Cancer Center. He specializes in solid tumor, medical oncology and genomic applications in therapy. He has published in several journals, including Nature, Science Translational Medicine, Cancer Research and JAMA Oncology. Dr. Husain is also involved in early drug development and translational clinical trials. And I think Dr. Husain is just finishing up with a patient. So he will be joining us momentarily. I will turn it over to Dr. López-Díaz to get us started. Thank you, Dr. López-Díaz.

Sure. So welcome, everybody, and to this new session of the breast cancer molecular tumor board. And for today's session, we'll discuss with our moderator, Dr. Husain, the convenience of keep buying on the topic of HER2 alterations as a central dilemma for breast cancer therapies. And this in reality comes out in a -- as a very nice segway from our previous molecular tumor board where we discussed HER2 therapies in nonmolecular targeted therapies for HER2 or in the absence of HER2 alterations, specifically in HER2 alterations, and we discussed the clinical trials monarchy for abemaciclib and also in combination with hormonal therapy, and we discussed also the DESTINY-Breast trial for trastuzumab deruxtecan, which are also -- which is also a novel therapy for HER2, which is a bi-model conjugate. So the interesting -- the interest of the discussion is to now switch a little bit more into, well, HER2-targeting therapies in the basis or in the presence of HER2 alterations. As you all know, HER2 is the protein that is coded by the ERBB2 gene, which is an epidermal growth factor receptor family member. And for today's cases -- for today's discussion, we brought a number of cases, 3 different cases, which will present different scenarios that we find commonly in the clinic and you practicing physicians will probably find very often in the clinic. With that and without further ado, I'm going to turn the microphone to Dr. Nhu Ngo, if she wants to add any comment into this before we get started.

Sure. So as most of you are -- I think most of us are -- I'm a pathologist by training. So most of us are exposed to HER2 and breast cancer because we do HER2 IHC and FISH. And in those 2 scenarios, we're actually looking for amplification of the gene with FISH and therefore, overexpression of the protein on the tumor cells, which is IHC. In this -- in the 3 cases we're going to show you, we're actually looking at activating mutations in HER2, which is a slightly different mechanism but also ultimately results in HER2 activation. So at the molecular level, we're not going to pick these up with the FISH. We may take these up by IHC because some of these mutations may potentially lead to overexpression, but truly what these mutations do is activate the kinase, either the binding domain outside of the cell or the kinase domain in the protein. And so you actually really need some sort of sequencing study to pick these up. And so in these 3 cases, these were all detected by sequencing of the tumor.

One of the things that Dr. Ngo commented is that HER2 is typically detected by IHC, eventually by FISH in its amplifications. And let's say that the alterations that we typically would find in breast cancer the HER2 coding gene, ERBB2, has been presented across multiple studies in the -- that are present in public databases in about 9% of all breast cancer patients. And more typically, the alteration that one would see is a gene amplification of ERBB2, followed by some activated mutations in different domains of the gene. And I think that just to put it in comparison with other frequent alterations in breast cancer, like PIK3CA, and we will have some case presenting PIK3CA alterations, 9% of breast cancer is present with HER2 mutations or ERBB2 mutations as opposed to 21% of breast tumors, which present with PIK3CA alterations. And that kind of sets the tone for what is the prevalence of these alterations and the frequency you might eventually find in cases with these alterations that can be targeted by molecular therapy. So I see Dr. Husain is out of clinic, and we thank you, Dr. Husain for your kind gesture to be able to join us today. We know that this is your busiest day in clinic. So as not to delay, we'll introduce Dr. Husain again and give the word to him. Husain.

Wonderful. We are just so pleased to have Dr. Husain joining us today. Dr. Husain is a medical oncologist and Associate Professor of Medicine at UC San Diego Moores Cancer Center. He specializes in solid tumor medical oncology and genomic applications and therapy. He is creating a liquid biopsy program with novel technology to evaluate oncogenic drive events in solid tumors. He has published in several journals, including Nature, Science Translational Medicine, Cancer Research, JAMA Oncology and Clinical Trial Research, and he is involved in early drug development and translational clinical trials. Dr. Husain, we are just so glad to welcome you back. Thank you so much for joining us. We really appreciate your time. I know that you have been with patients, and that is always our top priority, patient care. So thank you for joining us.

Thank you, Susan, and thank you, Dr. López-Díaz as well. I do apologize for the slight delay here but looking forward to the discussion.

Okay. So let's go and introduce the first case. We've been explaining why the topic of today, Dr. Husain, as we discussed before. So our first patient, can we go back one slide? Our first patient is a female patient, 80 years old. And presented with malignant neoplasm of breast. The stage was classified as 1c 1a. And here are the molecular alterations that were detected. Next slide, please. I don't recall if we had HER2 data for this patient. So while we look on that, we'll go straight to the alterations that have been detected this patient when was sequenced -- when the tumor was sequenced, we detected ERBB2 alterations, a very common mutation, lysine 755 mutated into a serine. And this is actually a commonly very well-known pathogenic alteration. It is an activating mutation, which renders the protein in a constitutively active configuration. The patient also presented a PIK3CA alteration, which is also a very frequent one, one of the most frequent activating mutations, PIK3CA. It is a glutamine 542 to lysine. I think I said lysine, I think the previous one was leucine 755 to serine for ERBB2, I apologize. In this case, PIK3CA is a glutamine to lysine, glutamine E542 to lysine. The patient was stable for microsatellite. It had a very low tumor mutation burden. And no abnormalities were detected in BRCA1, BRCA2 or in the estrogen receptor positive. So Dr. Husain?

Sure. Well, thank you, Dr. López-Díaz. I was really excited about presenting and participating in this case, partly because I think in solid tumor oncology now, there's growing indications that are really spanning multiple tumor types. And I think that when we think about HER2, this is really a gene now where we are thinking about it in lung cancer, we are thinking about it in gastric cancer, we are thinking about it in biliary cancer and much of the work that has set the precedent for how medicines have been explored had actually been in breast cancer. So this is a slide actually which really kind of depicts and capitulates all the point mutations that can be seen across the HER2 gene. And I think one thing that's relevant in this case is, is that this patient with breast cancer has amplification, but also an activating mutation. And when we think about that dynamic between the somatic mutations that can lead to increased phosphorylation as well as activation of the pathway, plus amplification of perhaps actually that mutant gene that really kind of gives us insight into the dependency on the pathway and the role of the pathway here. So here is a slide which really shows the diversity of different mutations across the HER2 gene. I think interestingly, the mutations can occur in the extracellular domain as well as the transmembrane domain as well as the kinase domain, and the kinase domain is where this patient has her mutation. Next slide. So here is another representation of that similar point. And this is a nice cohort that looked across a variety of different tumor types, but actually looked at how having mutations across the diversity of genes could be reflective of response. And in this case, it was to pan-ERBB inhibitor known as neratinib, so TKI, to see how different mutations in HER2 can actually lead to more or less responsiveness. And what we can see is that for this particular mutation that the patient has, L755S or P, this was a cohort of patients that had some response. We can see with a complete response in red, also a partial response, some element of stable disease and then also some progressive disease. So it gives us some insight to say that perhaps there are some mutations that have more responses associated depending on which alteration is seen. We can see that the -- so the monotherapy cohort, which is listed here, looked at neratinib by itself in breast cancer, combination cohort looked at neratinib plus fulvestrant, estrogen receptor modulator. And what we see is that the S310F mutation had slightly higher incidences of response. Some of the ones actually that had perhaps less response are the mutation listed here for this particular patient, the L755S, but it really kind of speaks to the fact that not only do we need to know if a patient has amplified HER2. In many cases, the granularity of the mutation is really important. And this has really become paramount in lung cancer, where it's not enough just to say a patient is EGFR mutant anymore. Really knowing does that patient have an EGFR exon 20 insertion? Does that patient have an L858R versus exon 19 deletion versus L861Q? There's many different mutations. And each of those mutations may have more clinical significance at this time. Next slide. So this is actually a slide that Dr. López-Díaz has created, and I thought this was actually a very interesting thing to highlight because it really depicts not only do we need across cancer to know the individual point mutations or somatic alterations within the gene from a mutational landscape, but how coalterations affect the outcome for patients is really becoming recognized and important as a major way to think through outcome. And this is a fairly more recent kind of consideration. Full clarity, many of these efforts have been led in lung cancer, where now we have the approvals for KRAS G12C inhibitors, knowing if patients are KRAS/LKB1 mutant, KRAS/KEAP1 mutant, KRAS/p53 mutant really speaks to the fact that those patient populations are very diverse, may have different responses to either immune therapy or the G12C inhibitors. And I think in this case, in breast cancer, a similar principle applies where we see in Dr. López-Díaz, I'm kind of using your slide here, so definitely interject at any point kind of when that comes up. But I think that one of the points here is that, obviously, there's a lot of amplified HER2 some mutant. And -- but if you look at the co-occurring alterations that occur most commonly, p53 is the most common at 47%, but then also PI3 kinase, which this patient has. So actually, maybe Dr. López-Díaz, actually any additional reflections you have as you created this?

Well, one of the -- probably one of the interesting points that we found when we were doing this analysis, which was trying to find among all the ERBB2, in this case, was all the ERBB2 amplified cases, we excluded mutations for that particular study was what other cell cycle regulators were mutated because they -- we know, in general, this is as a general principle in cancer biology. There are too many mechanisms for tumor growth. One is proliferation. The other one is cell death resistance. So in this case, we mainly analyze the cell proliferation pathways and specifically cyclin-dependent pathways, and you might see here very common genes that are involved for cyclin-dependent therapies like CDK4, CDK6, which are targeted by some of the most common breast cancer therapies, RB1 as well here, you'd see in the case of cell death resistance, the PIK3CA gene, which interestingly and eventually interact also for impact in cell proliferation as well, but it's mainly known as a cell survival pathway in breast cancer cells. And we've included here p10. The one interesting thing here is that no single gene among this pathway has been overwhelmingly commutated in HER2 amplified cases. The HER2 will be the one that drives mainly proliferations. And in this case, all these other cyclin dependent or cell cycle proliferation genes present some procurements of mutation and probably the most salient was indeed MYC amplifications, which is indeed [Technical Difficulty] gene. So that's probably the most important part. This negative data in a way shows there is no specific gene that will show a major prevalence, but each of them can be eventually commutated and when they do. And of course, we need to consider also the fact of cellular heterogeneity in the tumor, which maybe some cells have one alteration and other ones -- and other cells have another alteration, all these mutations happening in the same cells. But as the tumor behaves as a single tissue -- as a single abnormal tissue, it's important to see them in conjunction.

Yes. I think excellent points. And I think really also highlighting the need or importance for a broad next-generation sequencing strategy where we can understand and get granularity on across genes. And I think, as you've mentioned MYC, it's interesting that about 1/3 -- it's about a 1/3, 1/3, 1/3 in terms of third PI3 kinase coaltered, third MYC, there is overlap there between those 2 as well as it could be about 50% for P53. So if we go to the next slides, Susan. So this is an independent cohort in China, which kind of did a similar type of analysis looking at coalterations. I think some of the details are similar in the sense that even across perhaps an ethnically varied cohort across different regions, kind of seeing similar data where with HER2 amplification, P53 being kind of the most common coalteration. And in this case, actually, CDK12, we didn't actually have that on our -- on the oncoprint that Fernando López has -- but PI3 kinase, also kind of the next most common. Next slide. So I spoke about the fact actually that neratinib was a medicine that was tested across the mutations. We can see over here, this is some of the data looking at ER-positive, ER-negative and the combination that I spoke about neratinib plus fulvestrant, we can see the response rate. It seems like neratinib was more responsive in the ER-negative also in combination with fulvestrant. Next slide. So what's also interesting in this paper from Cancer Discovery is that they looked at HER2 mutation, they looked at some other ERBB family members, including HER3. And this is important because there's some drug development now for HER3 antibodies, both in breast cancer as well as lung cancer. And one thing of note here is that if you look at this oncoprint, patients who had less clinical benefit with the medicine had other coalterations and other pathways outside of HER2, right, including p53, PI3 kinase, p10, in some cases, FGFR and EGFR. So I think that the field is really trying to understand across medicine response, how do these coalterations differentiate response. And this is also important in light of the fact that I mentioned that even mutations within the same gene may have different responses. So that layer of granularity is becoming more and more important. Next slide. So I think one strategy, and again, this is probably well known to the group is that TKIs may have selectivity across mutations. Another class of medicines, antibody drug conjugates may not necessarily need to be so selective for each mutation partly because of the fact that the payload is a chemotherapeutic. And the strategy is bringing the medicine to the site of amplified HER2 or HER2 expressing cells. And this has become complex because the amount of expression may not be as important anymore in light of recent approvals in HER2-low. And I think that was discussed last session. But here is just a schema really showing the novel strategies. I think this is really important partly because these medicines are showing improvements across many different diseases, breast cancer, lung cancer, gastric cancer. And in fact, they really have even gotten approvals. And when we think about this, a recurring theme that is coming up is, can these medicines for HER2 be applied as a tumor-agnostic indication? Meaning, can they be applied across pan-tumor indications? And I think we've seen a recent approval for BRAF V600E in this category, where now there was approval for BRAF therapy as a pan-tumor indication. And so I think that the field is really thinking through where is this going to end up in HER2? Is there going to be pan-tumor indications? What's the right medicine? It appears that the antibody-drug conjugate seems to have the totality of data to at least hedge in that direction. Next slide. So here actually is the data. And kind of really, you can see a remarkable response rate with the antibody-drug conjugate. Again, this one, trastuzumab deruxtecan links trastuzumab to deruxtecan, which is the chemotherapy payload. And really remarkable responses. This is even against T-DM1, trastuzumab emtansine, which really showed a dramatic hazard ratio of 0.28, a response rate with the trastuzumab deruxtecan, 76% versus about 34% with the trastuzumab emtansine in progressive patients with breast cancer. So we really see that these ADCs are distinguishing from each other. And this is kind of very remarkable finding for a patient population in which there has been very active drug development across both the TKIs as well as the ADCs. Next slide. So here actually shows that, interestingly, finding better biomarkers for these antibody-drug conjugates is going to be necessary. We would think that HER2 expression would be the most correlative. It doesn't always seem to be the case. I think the last session spoke about HER2-low. And I think that really a charge forward is how do we develop better biomarkers in the HER2 space, recognizing now that we have expansion of the molecules of the medicines. And even some of the principles that we spoke about before about coalterations as well as the role of somatic mutations versus amplification. Next slide. So here is some other additional data about approved TKIs in HER2 amplified breast cancer. This is tucatinib. We can see that this was given in combination with [indiscernible] and led to improvement in PFS as well as overall survival. The overall survival approached about 22 months compared to placebo, which was about 17 months. Next slide. And here actually just shows that some of the subgroups that got the best benefit are those actually brain metastases and that is an unmet need. So having the molecules that can be better selective for that space. Next slide. Okay. So I think this was a quick whirlwind tour of some of the medicines, but now we're going to do a little bit of a deeper dive into the mutations and really try to address which tumors are more common with this and how does the breast cancer model apply even outside of breast cancer. So -- and we're going to represent that in the next cases. Any questions at this point?

It does not look like we have any questions right now. [Operator Instructions] So I think we can move on to the next case just to keep it going. And if anybody has any questions, they can submit them, and we will discuss after this case.

Yes. So let's go with the second case then. So this is a younger female, 56 years old. And -- which presented with a metastatic carcinoma of the breast. Do we have the HER2 data in this next slide, I think it's not here, should be in the next. The next one, please. I think it's -- yes, here it is. So this patient was triple negative. Patient with a high degree, 79% of Ki-67, which indicates a proliferative rate of tumors. And we know that Ki-67 in breast cancer has had a bivalent interpretation what it really means in terms of prognostic or not, but it's still a very, very common marker that we [Technical Difficulty] In terms of the genomics, we can see here actually a summary of the genomic timings for this patient when it was sequenced. Patient presented MSH6 mutation that is a truncating mutation at the amino-terminal region. So obviously, most of the protein is missing. And with an allele frequency actually of 31%, also presented on PIK3CA alteration in their R88Q domain. And it presented also a very frequent alteration in histidine 1047 mutated to [Audio Gap] Okay. I apologize. I got a lag in my memory. So H1047R mutation is very frequent alteration. And the allelic frequency of this mutation is 47%, pretty high. And we'll go into detail on that in a second. Patient also presented a BRAF G459R mutation.

Yes. No, I was actually just going to say -- sorry to interrupt. I think this case is so fascinating because we see that the case is not necessarily HER2 amplified, has a high Ki-67, 79%. And then obviously, when you look at it kind of having this activating HER2 mutation as well as PI3 kinase mutation and BRAF really kind of speaks to the fact that either there's some element of clonal heterogeneity here with different or multiple pathways that seem to be activated driving that Ki-67.

Yes. That is definitely, as you say, fascinated. Well, just to finalize and summarize here also, we're seeing a p53 alteration at around 38% allelic frequency, a very common mutation on arginine 175 to histidine, which would actually -- it's a dual alteration for once it to process the tumor-suppressing activity of p53 because it cannot longer primarize the protein to bind DNA. But at the same time, it's known to be an oncogenic alteration, so it counters a new activity this protein and making it into an oncogene function. And this is a field that has progressed over the past 10 to 15 years to uncover all these new functions of p53. Finally, we do see an ERBB2 alteration in the domain of R678Q at 41%. So I don't know if in the previous slide, we had a Tumor Mutation Burden. It may be interesting to see, Susan, if you can go back 1 slide. Okay. Well, yes, the Tumor Mutation Burden is intermediate. Of course, the patient has a stable microsatellite. But one of the reasons that I was kind of suspicious about the Tumor Mutation Burden was after seeing so many alterations in very specific pathways in p53, BRAF -- these different alterations, we see an intermediate tmb of 8.5 mutations, if I'm reading correctly, per megabase. In a way, it makes sense. Regarding p10, the p10 result, if you go -- it's okay. We can leave it there. It has a p10 deletion detected by FISH. And we can discuss a little bit later about that p10 deletion. Okay. Next slide. Yes, Dr. Husain.

No. Thank you, Dr. López-Díaz. And actually, just coming back to our framework over here. Obviously, another patient with a HER2 mutation. This patient also had like the last of PI3-kinase alteration and has also atypical BRAF mutation, non-V600E mutation. I think what's unique about this case and one of the reasons why this struck us from a HER2 standpoint was the mutation that's represented here is the R678Q. And you can see that, that is somewhat common HER2 mutation, but it exists in a domain called the transmembrane domain or the juxtamembrane domain. And this is important because this is not the kinase domain. And there's been a lot of speculation about how do mutations in those locations function to be activated. And now we'll do a deep dive into that. We go to the next slide. So this is some figures from a paper and cell. And basically, kind of what was looked at in this, we're looking at mutations in the transmembrane domain, in the juxtamembrane domain and looking at how those mutations can cause protein conformational changes and how even the extracellular receptor was -- had its conformation and its binding capacity outside of the cell. And so what we see is that based on the specific types of mutations that can exist on the transmembrane or the juxtamembrane domain, those can affect the rotation of the receptor, and that has implications in terms of how the receptor dimerizes with other HER2 family members. And again, dimerization is one of the ways that HER2 can cause activation of the pathway or how heterodimerizes with other molecules such as HER3. And so this is interesting, partly because when we think about the types of mutations, we typically mainly think about kinase-domain mutations. And now thinking about how did these juxtamembrane or transmembrane domain mutations affect the receptor in a way to affect dimerization or binding with other ERBB family members. That's kind of what the subject of this paper was. Next slide. And why is this important? So there's been some clinical reports actually where patients with these transmembrane domain mutations or juxtamembrane -- can respond to TKIs. And here is a scenario where this is a patient who had transmembrane domain mutation and granted this is across tumor types. So I believe this case actually was a lung cancer patient. But what one can see is that with the medicine afatinib, there was a reduction of tumor with therapy. And I think it really highlights the granularity that the mutation now knowing which type of mutation, where is the mutation located, these types of things becoming increasingly important. Next slide. And here actually just shows another representation of patient with response to therapy. Next slide. So along those lines, when we think about the diversity of mutations, here is a heat map, which shows many mutations found across the different regions of the HER2 gene and whether or not some TKIs versus others may be more or less responsive. And what one can see in this is that some of the reversible inhibitors seem to kind of have more areas where they may be resistant. Some of the irreversible inhibitors have more green and yellow which show sensitivity or partial sensitivity. But I think that really understanding which mutations are going to be responsive versus others is kind of where the field has moved and gravitated to. Next slide. So happy to take any questions now about the transmembrane domain mutations or kind of that layer of diversity.

Okay, I'm seeing maybe there is a question here -- we have here. So for invasive lobular carcinoma, ER positive 100%, PR negative and HER2 negative, what would be the current standard treatment options compared to new drug development options coming down the road?

No, I think this is...