Clinical Implications of Testing HER2 and Targeted Therapies Approved - Dr. Komal Jhaveri

Understanding HER2-Low Breast Cancer Landscape If I have a consistent IHC true zero with no her two expression at all, I might consider doing a biopsy when appropriate to see if this has changed. Given that we know that this could be dynamic and maybe I could find some her two expression that would allow a new treatment option for my patient in clinic. Speaker 2 This podcast is for healthcare professionals only and AstraZeneca has provided A sponsorship grant towards this independent program. Speaker 3 Hello again and welcome back to the Oncology Brothers podcast. I'm Rohit Ghosain, joined as always with my brother and Co host Rahul Ghosain. Both of us are practicing medical community oncologist. Our mission with these discussions is to make sure that you leave with the latest and the most practical updates in the cancer care. Today we'll be talking about metastatic hormone receptor positive breast cancer. There's quite a bit happening in the space, but focus of the discussion today is going to be her two negative, which was how it was defined before but now rather termed as low or ultra low. Her two expression. This does not change our first line treatment option that is still CDK 46 inhibitor plus endocrine therapy and importantly the need to check for pick three CA mutation or P10 loss. But if the disease was to progress, that's where the discussion is going to be on focus today. To sort through this space, we were honored to have Doctor Komo Javeri, a breast medical oncologist at Memorial Sloan Kettering, join us today. Speaker 1 Thank you so much for having me again. DESTINY Breast-04 and 06 Redefine HER2-Low To set the stage for this discussion in metastatic hormone receptor positive breast cancer, her to status historically was binary right, It's either positive or negative. But this all changed in 2022 based off Destiny Breasto for study where we saw significant improved PFS and OS in lower her two with Trastuzumabdorex T can. And this presentation by doctor Shawnu Modi rightly so got standing ovation at ASCO 2022. But then we all started to question saying how low is low for us to see response from Trastuzumabdorex T can in this settings. And that took us to Destiny best 06, which led to the approval of Trastuzumabdorex T can in low and ultra low her two breast cancer. Cuomo, can we start here? Can you touch on the study design of Destiny Breasto Sex and its findings that led to the approval of TDXT in this space? Speaker 1 So I think to your point, you know when we thought about her two as a target, we were only focused on her two as an oncogenic driver, which is what we thought was happening, which is why we went after it when we thought about her two as a binary expression and her two subtype as the way to target, right. And we have approval for say TDM 1 initially and then TDM EXT for her two positive breast cancer. But beyond that, now we've learned that her two is still a relevant target. But it doesn't have to necessarily be an oncotenic driver. We could literally use it as a medium as a way for delivering payloads with our newer current novel ADC such as trastuzumab, Duroxycam. And that is why we kind of have this, you know, subtle loss of boundary between subtypes, right? We now have her 2 low and her 2 ultra low, which was not necessarily how we thought about subtypes, where we thought about ER positive, her 2 positive and triple negative. Breast cancer has three important subtypes and Destiny breast O 6 was a step forward after Destiny breast O 4. So Destiny breast O4 led to the approval of trastuzumab deroxacan for her two low cancers regardless of hormone receptor positivity. And this was in patients who've had at least one line of chemotherapy and no more than two lines of chemotherapy and predominantly represented the HR positive, Her 2 low cohort, her 2 low being defined as tumors that are IHC one plus or two plus that are FISH negative or ish not amplified. And we had approval there. And then we said, what if we were to bring it even up front in the metastatic setting? Could we use it in the chemo naive setting specifically for HR positive tumors, not HR negative, her 2 low, but focus on the HR positive and bring it in the chemo naive setting. And what if the tumors had just some level of her two expression? And this is the her 2 ultra low, which is more than 0, less than one plus or you know, tumors that are less than 10% of incomplete membrane staining. So as long as it's not completely null or completely zero and some expression, those were the two kinds of tumors that were the focus for D BO6. And this was for chemo. Naive setting as we said, patients had to have had endocrine therapy and majority did have CDK 46 inhibitor. And here we saw an improvement in the progression piece survival compared to the physician choice chemotherapy arm, which could have been taxane scapecitabine. So it improved from 8 months in that control arm to 13 months with TDXD use in the chemo naive settings. So post endocrine therapy chemo naive setting and we don't have overall survival data yet. But even for the HER 2 ultra low tumors, the efficacy, efficacy signal was similar. The response rates looked great. The PFS was in line. Of course the subset was smaller and it is exploratory, but I think relevant and that's why we have approval for TDXD in this setting. Speaker 3 It's amazing to see how low of an expression is needed for this drug to actually work. And since the inception of these ADC's we have been like seeing a whole slew of come out for approval. That is after TDXD. What we've seen is Sassatusumab recently Dado XD which is just in breast cancer world. Though TDXD has a bucket approval for all solid malignancies with IC. Her two positivity. The Evolving Nature of HER2 Expression Testing Coming back to our her two-story Komo, can you define who qualifies particularly for this? Her 2 positive low, her two and ultra low as you described. But given how heterogeneous this is, how often are we checking for this expression every time on progression? Or how are we going to maneuver through this? Speaker 1 Yeah. No, I think such an excellent question. So you know as we said, her 2 positive tumors are tumors that were either IHC 3 plus or they could have been 2 plus as long as they had an application by ISH and that's what we still consider as her 2 positive. Now for her to low, we said the definition could be anything less than that, meaning it could be 1 plus IHC or it could be two plus IHC that is not ISH amplified and that's for her to low and ultra low is more than 0, less than one or 10% or less incomplete membrane staining. So as long as they have some her two expression, that's enough for us to think that this antibody to a conjugate can go target that her two protein and deliver the payload and derive the benefit that we have seen so far. And I think, you know, when it comes to how often do we test it, I think because we have recognized that her 2 low and ultra low can be more dynamic than saying her 2 positive tumors could be. And even with her 2 positive tumors, we do see this change in expression or change in her two levels and her two loss as a mechanism of resistance with multiple anti her two therapies. But her 2 low tumors is thought to be more dynamic and it could, you know, evolve between the primary tumors to the metastatic setting between 1 biopsy and the metastatic setting to the other. So the way I think about it is as long as I have some her two expression, whether it's in the primary, whether it's in the metastatic setting, I definitely do not miss the opportunity to offer TDXT to my patient unless there is an obvious contraindication with interstitial lung disease or something else that you know prevents me from doing that. But if I have a consistent IHC true zero with no her two expression at all, I might consider doing a biopsy when appropriate to see if this has changed. Given that we know that this could be dynamic and maybe I could find some her two expression that would allow a new treatment option for my patient in clinic. Speaker 4 Cuomo, thanks for touching on that. Can I just pick it up where you left one? Navigating Subjectivity in HER2 Testing for Patients Her 2 testing is dynamic also very subjective, right? So now given the data in hand with Destiny Presto 6, you've touched on this that the data looks very similar for low her two and ultra low her two. But in our clinical settings, one thing that we're always pondering over is can I use this for a true her to negative patient as well? How important is this expression on my end in the community? How far do I push my pathologist to label something as low her tooth? Speaker 1 Yeah, Yeah. No, I think it's an excellent question. I think given the totality of data that we have at TDXD and the robustness of efficacy that we've seen across subtypes and across settings, I think it's very tempting to think about, you know, what could I do to make this work right. But the good news here is that if you count your her too positive tumors, you count your her too low and you count your her too ultra low, we're talking about 85 to 90% of us get. So we're really covering the breadth of breast cancer subtypes and we're talking about a small proportion 10 to 15% when we truly think that they might be truly her to null or truly IHC zero with no level of expression. And for that patient, I am not going to offer TDXD. So certainly I would, you know, if needed now that caps has this her 2 ultra low also included. Our pathologist have taken that on and even pathologist that were not doing that right away. Some have converted sooner, some are now, you know, homogeneously converting and now in their reports, hopefully we don't have to make those phone calls that we did a few months ago asking them, do you really not see anything? So I have not had to do that. And thankfully, community doctors will also have less of an opportunity to necessarily do that. But certainly if there is something that you were, you know, considering in clinic and wanted to clarify and make sure, I think we can certainly think about doing that. But I think it's going to be for a smaller group of patients, which is the good news. Speaker 3 That is a small group of patients, but when we are deprived of treatment options, especially out in rural setting, there are no clinical trials available. You want to jump on especially how promising this drug is. And from what we've seen with Daisy trial as well, though that was true her two negative, there was still responsiveness which is remarkable. But again, that's not where the approval is. Speaker 1 Daisy did not breakdown your IC0 from ultra low. So what Daisy said was this is IHC 0, but it did not necessarily really clarify that the true negativity. And so yes, this is Daisy was the reason we we thought that yes, there might be more to IHC 0, which is how we, you know, stumbled upon her 2 ultra low as well. So I think Daisy helped us guide there, but did not necessarily clarify that directly. Speaker 3 Thanks for clarifying that Komo. Optimal ADC Sequencing After CDK4/6 Inhibitors Besides this subjectivity which is tied to the her two, another question that we ponder upon is the sequencing after upfront CDK 46 inhibitor in the absence of AKT pathway mutation. In what line are you utilizing this in your clinic today? Speaker 1 So I think our goal in hormone receptor positive breast cancer, at least today still remains that we try and maximize endocrine based options before we deem A tumor endocrine refractory and then switch over to sequential single agent chemotherapy or antibody drug conjugates. And so I still continue to do that. There might be a patient where I might be able to do up to three lines, 4 lines of endocrine therapy based options before I move over to chemotherapy. And there might be patients where I'm doing that in the second or third line, right. So it totally depends on what prior therapies they've had is a de Novo tumor, what is the disease burden? And one important thing that I'd highlight from the DBO 6 that we have data for now, 9% of the patients in DBO 6 that were enrolled had this primary endocrine resistance in that in the metastatic setting, the duration of their first line CDK 46 inhibitor therapy was less than six months. And that really gives us that confidence that for these primary endocrine resistant tumors, we can certainly jump on to an antibody drug conjugate such as CDXT as the next line of therapy. So as a second line treatment regimen for true primary endocrine resistant tumors, which included less than six months duration on CDK and were included in the TBO 6 trial. But short of that, I'm trying to maximize my endocrine based regimens before I move to chemo. Speaker 4 You know, can I piggyback on the sequencing question as well? We have to keep the disease burden in mind. We have to keep side effects in mind, but we have a few Adcs that are approved here. And in clinical practice, for hormone receptor positive, we're often using TDXD first and then sasitizumab in most cases, whereas in triple negative, we're often doing the other way around where we lean into sasitizumab first and then TDXD. Como do we have any real world data around sequencing one ADC after another? Speaker 1 We do, I mean we do have some data from small retrospective studies from single institution, from real world data sets. And I think the big picture learnings from those attempts have been that certainly ADC one gave us a better durable, you know, PFS benefit. ADC 2 gave us a slightly shorter duration of benefit and regardless of what ADC was used, first or second. So it could have been TDXT first or Sassy 1st and the other one and next. But there are a group of patients where somehow ADC 1 did not necessarily work, but it worked really well with ADC 2. And we just don't know what the issue there is or what was the hold up there, you know, is it related to a target? Is it related to a payload issue? I think could it be just differences in the potency of the payloads and the drugs itself? Even though all are approved? ADC's currently in the HR positive space have similar rich payloads if you will. They're all 241 isomerase inhibitors. There could be some differences in their linker technologies and also their potency of the payloads itself. And so certainly that's what we have seen. A most recent, you know, real world data set that we also saw that was presented at ESMO breast as well where post TDXD they saw that chemotherapy actually had a longer PFS benefit, Iribulant had a longer PFS benefit compared to other ADC's as well. So I think we're still learning a little bit more from that. We need a little bit more information. We have ongoing efforts such as the TRADE DXD trial where we're trying to see if between the two Diroxican payloads, if we're changing the target wouldn't matter what we use first. So in this trial, patients would either get TDXD 1st and datapodumab at the back end or start with datapodumab first and get TDXD at the back end. So that's Trade DXD. And then we have registries, we have the registered within the Translational Breast Cancer Research Consortium and the series study looking at TDXT and sassatuzumab. Should we start with one and go to the other and what would that look like versus start with Sassy and go to TDXE after, What would that look like? So we'll have more data from those studies. But I think at the end of the day, it would be very attractive for us to also have newer payloads, newer targets as well because as we have learned in the bladder cancer world where patients got say and Fortimab or sassituzumab and completely different ADC, so and Fortimab is nective for MMAE ADC. Those patients did better than say they would have had a similar target or a similar patient. And so I think we're we're looking forward to those new advances as well. Speaker 3 It's amazing how fast the science is changing. There are so many multiple approvals in the same setting and sequencing. It's not just an issue here in breast cancer, but as you stated, bladder cancer, kidney cancer and all throughout solid tumors and heme world. Effectively Managing TDXd-Related Toxicities and ILD Komal we have, we now know how to test the her two and now we know when to use TDXT, but importantly how to manage the toxicities, especially this ILD tends to be a hot topic because again, there is mortality. So we see it here with that. But again, this also has other side effects like alopecia, nausea and vomiting like other chemotherapies. Any clinical pearls around the side effect profile here? Speaker 1 Absolutely. Very, very important to think about the side effect and how to manage them because without that, without, you know, addressing that, we cannot have patients continue on the intended therapy and derive the intended benefit we hope to achieve for them, right. And so let's talk about common toxicities first and then we'll talk about the important ones that can be fatal. So the common toxicity necessities that we actually face in clinic when we're treating these patients with TDXD are actually nausea and fatigue. So nausea, vomiting, fatigue are the most common ones that we need to address first. And the very important piece that sometimes I feel like it's still not necessarily homogeneously utilized is the triple anti emetic regimen or the quadruple anti emetic regimen that also includes olanzapine. And I think that has been a game changer for my patients in clinic. I think that grade 2 nausea, the grade 3 nausea rates have definitely come down. The dose reductions have reduced as well. And patients are tolerating treatments much better with triple anti emetic and quadruple anti emetic regimen. So it must do for our patients in clinic fatigue, if there is intolerable fatigue, it's very hard and subjective sometimes to think about fatigue and how a patient, but you know your patient, the patient gives you good history about it. You can assess that. And if it's intolerable and you want these patients to continue on therapy, those reductions make it easier. And I have certainly resorted to that and have kept patients on for a longer period of time. So those are the most important ones. Alopecia is a very good one. I absolutely discussed that with every single patient of mine. Although I have to say when we first had approval for TDXD, that was DBO one in the her 2 positive late life metastatic setting, we certainly saw a much higher rate of alopecia. In Koenig. I'm seeing much lower rates of alopecia than what we had seen. And that could be because more prior treatments, more treatments that had already caused alopecia make it very difficult to kind of attribute that to a given treatment in a clinical trial. So in practice, I've definitely upfront prepared patients for alopecia, but I've seen much less alopecia than it was originally reported. And the other thing is that the jury's out still whether scalp cooling would help. There are ongoing trials trying to address that question. Now, these are longer acting half lives, right? These antibody drug conjugates are over three weeks. We don't necessarily know yet whether this would absolutely help or not. Is it because the patient was not going to lose their hair or is the scalp cooling, you know, helping with that? Some patients want to do it. I've never stopped them. I tell them I don't know that this will help, but I have no problem. I have many patients who stay on scalp cooling and we would never find out if it was the drug that was not doing it or or if it was the scalp cooling helping, but I let them do it. And last but not the least, I think it's ILD. As you pointed out, it's important because it can be fatal. Now thankfully it's not as common, but it is still present and we really want to know about them. It's very important for us to keep an eye on the radiological exams that we obtain now in trials, you know, CT scans were done every six weeks and they had an adjudication committee to review them. In practice six weeks could be a little tricky, although some patients I have done six weeks what I would do their systemic scans every 12 weeks that the way we would do every three months. But if I'm nervous about if they've had prior history would say evolimus related pneumonitis or PICK related pneumonitis or some, you know, lung issues that they've had, then I would do a CAT scan just for the chest high resolution CT every six weeks. So I've played it by ear. I either do it every nine weeks or I've done 6:00 and 12:00 depending on a patient in front of me. It's very, very important to recognize that Grade 1, all you have to do is pick that up on your radiological scan. The patient's not going to be symptomatic. You have to hold the therapy. You can give them a quick dose of steroids. If the radiological findings disappear by less than 28 days, you don't even need to dose reduce. You can re challenge at the same dose. If it takes a longer time, you have to dose reduce. So it's very important. We are very vigilant about the CAT scans. And then the second thing is Grade 2, which is not just the radiological findings, but also symptomatic ILD. And in those cases, we're not only holding, but we're permanently discontinuing. So there was data presented about RE challenge. And I think with Grade 1, I feel like the RE challenge I think is easier. With Grade 2, I still get a little more nervous about the RE challenge. It depends on the severity of the ILD. But ideally with Grade 2 I would discontinue and give a higher dose of steroids and a longer taper. Certainly involved pulmonology for help. In there just so that you can get the guidance but this are the 2 minimum things that you need to do. Speaker 4 And that re challenge study was published by Doctor Hope Brugo, similar findings to what you said, Grade 1 ILD would use a steroids patient actually did OK. But within that study, it's a small subset. Grade 2 ILD was a very, very, very small subset. So we have to be very cautious in our clinical practice because again, there's mortality associated with this ILD here. Applying HER2-Low Data to Triple-Negative Breast Cancer Como before we close any final thoughts here and can this data be extrapolated to triple negative breast cancer with this ultra low hearted? Speaker 1 Yeah, I know. I think that's a great question. So I I think triple negative, you had brought that up as well that you know, we do somethings differently with HR positive and we do somethings differently with triple negative. I think we as physicians and trialists and you know just caregivers, we go after the totality of the data and we go after the robustness of the data. So the reason we use satsituzumab in triple negative breast cancer because there we have a robust phase three trial that led to the approval of that ADC in triple negative breast cancer and we now have more data for even earlier use as well. And we also have earlier use for dataportemab now which hopefully will get approved in triple negative breast cancer as well. The reason we were prioritizing TDXT after this while we have approval for TDXT for her to low, that was based off on a 58 patient extra exploratory analysis from the DBO 4. And so we want to use that. We want to justify that, but we don't necessarily you know forget our phase three trial that gave us robust data, PFS and OS improvements with sasatuzumab. Now could we apply her to ultra low again ultra low itself in DBO 6 was a smaller cohort and we did not have any data on HR negative her to ultra low. So unless we have more data, I would still be nervous about that. And we do have sacitizumab, we now have data with datapodumab for her to low tumors. We still have TDXDI would still rely on those for now. Speaker 4 We briefly alluded to this, there's more to common triple negative breast cancer space, but right this minute ultra low and low heart to where TDXD is approved is for hormone receptor positive breast cancer in metastatic settings. Como Thank you so much for this fantastic discussion. Metastatic hormone receptor positive breast cancer space is rapidly evolving and we hope that these bite sized discussions will continue to keep our community colleagues up to date. Essential Insights and Future of HER2-Low Treatment For those tuning in, let's go over a quick recap from today's discussion. Speaker 3 In today's discussion with Doctor Komal Javeri, we touched on the role of TDXD from Destiny Breasto 4 initially presented in ASCO 2022 for low her tooth disease to Destiny Breasto 6 for low and ultra low her tooth disease. In earlier lines of hormone receptor positive breast cancer, TDXD is now available for our patients based off of improved PFS. Rahul, your thoughts here from discussion today? Speaker 4 My two big takeaways here, 1, the importance of making sure we're partnering up with our pathology colleagues to appropriate and appreciate ultra low or low her two for these patients and not only because TDX CS approved, but this is indeed an active agent, right? Two, keeping side effects in mind and how to manage these from fatigue to nausea to alopecia and of course, ILD. We hope you've enjoyed this discussion with Cortad. We'll soon be back to discuss more in detailed her 2 testing to make sure we have a good handle on this. Thanks for joining us. Be sure to check out our other episodes for more insights and practice changing data. We are at the Oncology Brothers. Speaker 2 If you enjoyed this podcast and want to find out more than please look for the Oncology Medical Conversation Podcast under the account of Core 2 at Medical Education. Also, don't forget to rate this podcast, subscribe to our channel and share it with your colleagues. Thank you for listening and see you next time. This podcast is an initiative of Core to Add and developed by Breast Cancer Connect, a group of international experts working in the field of oncology. The views expressed are the personal opinions of the experts and they do not necessarily represent the views of the experts, organisations or the rest of the Breast Cancer Connect group. For expert disclosures on any conflict of interest, please visit the quarter end website.