Metastatic Hormone Receptor Positive (HR+) Breast Cancer Treatment Algorithm: Dr. Kevin Kalinsky

Hello and welcome back to the oncology brothers podcast. I'm Rohit Gossane alongside my brother and co-host Rahul Gossane. We're excited to continue our breast cancer treatment algorithm series, where we dive into understand what our experts doing from their current treatment approach standpoint. We recently covered early stage hormone receptor positive breast cancer with Dr. Erica Mayor and today we're shifting gears to metastatic hormone receptor positive space. Rohit, this space is starting to get very crowded. And this is a good problem to have given we now have new approvals with overall survival data, but we also have to keep side effects and best sequencing approach in mind here. To help us sort through all this, we're honored to welcome Dr. Kevin Kylinski, a breast medical oncologist and director of the breast cancer program at the Winship Cancer Institute. Kevin, thank you so much for joining us. Hey guys, thanks for including me and a very hot topic that is continuously evolving. Indeed. Yes, it is. And it is a good problem to have Kevin. Welcome. Let's dive into the metastatic hormone receptor positive breast cancer space where we divide this disease into two buckets. That is, did no metastatic disease or recurrent or relapse disease while keeping NGS in mind to look for those mutation that is pick 3CA because there are clinical implications tied to this. And then we have ESR one mutation, which we look on later on during the course itself, because this is a resistant mutation. Kevin, can you touch on your clinical practice around the NGS testing? When do you do this? Are you relying on tissue or is liquid biopsy here good enough? Yeah, I am often starting with liquid biopsy. If we detect CT DNA, that can be quite informative. If we are not detecting any CT DNA in the system, then I will shift and also look at tumor tissue with the caveat also. Therefore looking at ESR one mutations, you know, and you're sending say from the primary tumor tissue, you're not going to find them. That will be helpful for picks 3CA mutations, but not so much ESR one. And with regards to the same topic, the P10 loss, is that something still can be relied on CT DNA or that is one or the tumor? Yes, I'm so glad that you brought that up because that's the other caveat to really consider. There have been several series, including some data that my colleague, Manali Bobby, has published with foundation, which has demonstrated that P10 alterations may be underrepresented with CT DNA and found more frequently in tumor tissue. And again, it's important to keep these nuances in mind ESR one later in the course, better with liquid, P10 more so with the solid tissue, Roja, to your body, these mutations clearly have clinical implications. So let's dive in starting off with that high risk disease. That was initially exposed to endocrine therapy, but now we have progressive disease. And here we have a novelist that approved for pick 3CA mutations. Kevin, a novel 120 lead to the approval of this and we now have improved overall survival. Can you please touch and define things of this study? And importantly, some clinical pearls around side effect management when it comes to novelist. Some of this will again come in handy when we talk to other available pick 3CA treatment options in the next few minutes. Sure. This is a common question that I get. I have a patient who has a PI 3K mutation. Should I be giving a PI 3K inhibitor in the front line setting? And I will say that this is right now exclusively for those patients who have endocrine resistant disease, meaning they have a tumor that had progressed on their adjuvant endocrine therapy within 12 months of completing that or while they were on it. And so we have triplet data with Pobbicyclid and Fulvestran and novelistib. We have seen now an overall survival advantage. And this has been published in the New London Journal of Medicine. What these data demonstrate is how unfortunately patients do with doublet therapy. If they're getting Fulvestran in a CDK46 and how much better they are doing when they're getting the triplet. So to me, this is really standard of care for that subgroup of patients, which as you mentioned is a high risk population. The one thing I want to reiterate is it's important to think about preventing stomatitis in these patients. There is an oral steroid rinse that I would recommend utilizing preventatively. And that can be quite helpful for the management as well as for prevention of that particular toxicity. And then other things we have to look for can also be hyperglycemia and then monitoring things like the refunction test. But in terms of things that patients might feel and what we see most commonly is stomatitis. Thanks for covering that, Kevin. With regards to the hyperglycemia, do you tie in HBA1C or if the diabetes as well manage you would still offer this even if HBA1C is high? Yeah, we do check hemoglobin A1C on these patients. I think it depends on how poorly controlled somebody is. If a patient is insulin-dependent, it feels like it's going to really be quite a challenge. But if it's relatively well tolerated and they may be on oral agents, then I would still let it roll but watch them quite closely. It's very challenging, diabetic situation. It would be possible with any of these agents. Well, indeed tying in with the endocrinologist or even their primary care physician is the key here. Well, at Navolice, what we've seen from a Navol120 has more than doubled the PFS. That is from 7.3 months to 17 months. Key side effects and clinical pearls as we just covered. That is hyperglycemia, stomatitis and also keeping neutropenia, rash and diarrhea in mind as well. All right, Kevin, that was for high-risk disease. But how about the other bucket, the noble metastatic breast cancer? With hormone receptor positive disease. Where we have endocrin therapy plus a Bema or ribo cycle of as an option. How do you pick one CDK46 inhibitor or the other? And is there a patient that you would favor one or the other that is CNS involvement or bone-only disease? I tend to go with ribocyclobe because in our three large randomized studies, we saw an improvement in overall survival with the Bema cycle. We've seen that in some studies, but not all of them. I do think you mentioned the case of denoblo disease. That's how I would think about it. If you have a patient who has early stage disease and they might have received a Bema cycle in the early stage setting and then I'm thinking about a CDK46 inhibitor in the front line metastatic setting, I may switch it to ribo in that sort of circumstance. In terms of particular circumstances where I may think about favoring a Bema cycle, would be patients who, she mentioned CNS disease. Also a patient who has, you know, neutropenic issues. We see less neutropenia with a Bema cycle compared to ribo or palpo. That may be a circumstance where I favor a Bema. And again, when we're talking about ribo dose here, it's 600 milligrams different than what we tend to use in adjuvant settings. With a Bema, also we have to keep diarrhea in mind. Kevin, given this is metastatic disease, our treatment here is with palliative intent. What next? Checking for ESR1 mutation is important. We have two options of oral serds. We also touched on the pitprecae, AKT inhibitors, capyversertib or alpolisib. But alpolisib at least has completely fallen out of favor, given that we're using a novel upfront or capyversertib here. Can you touch on what next after the disease has progressed on that front line CDK46 inhibitors in endocrine therapy, including the story around re-challenging with a Bema and maybe adding umulonestrine is this something you're already doing in your practice? Yeah, I will talk about where we are at this moment because I also think that at the end of this year, things are going to continue to evolve. And so I agree with the point that you had made. It's important to make sure that you're checking next generation sequencing in this sort of circumstance, see if patients have ESR1 mutations. I do that by CTDNA often. And what I would say is if you have a patient who has a slowly progressing tumor with a low volume of disease, we're on their prior CDK46 inhibitor for at least 12 months, then I think monotherapy with oral surgery is absolutely reasonable. At San Antonio, we had updates from the Ember 3 study where we started to see an overall survival advantage of immunestrine compared to physician endocrine therapy choice. So we have two options in the nest grant, maybe with a higher rate of gastrointestinal issues compared to what we see with LSSR1. So that's just one thing to be mindful of. And as you mentioned, if a patient has a P3C mutation, we've really shifted away from Alpolisib, just given some of the toxicities, including rash and hyperglycemia. So often now we're favoring Kapiva serative, which is an AKT mutation as we had already discussed. We can give that for PETA and alterations, also for patients with AKT1, E17K mutations. With that, we can also see some hyperglycemia, LFT abnormalities and rash. As a clinical pearl in my practice, I utilize prophylactic clariton in these patients. We've seen some data with Alpolisib about this, and I have seen some notable rash from colleagues in the community. So I tend to recommend starting with claritin, also just the odd schedule of Kapiva serative, which is by stay dosing four days on, three days off. For patients who have germline-brockin mutations, we have the option of a parpahendiber. I tend to use that when I've kind of pushed through my endocrine therapies. I'm thinking about chemotherapy, and that's a line like a parpahendiber that I would give before that point. And then the other thing that you had asked about is what about switching the endocrine therapy and continuing a CDK46 inhibitor? And so we from data from post-monarch where patients receive full vestrine and a BEMA cyclib, most had prior POPA cyclib. The improvement was negligible, and arguably the question has been, is it really clinically that relevant? And the data within LUNE-Nestrine plus a BEMA cyclops seem quite impressive. And one of the things that I want to mention compared to monotherapy within the NESTRAN is the benefit with monotherapy's ESR1 mutations. If it's doublet, regardless of the presence or absence of ESR1 mutations, and there was a median progression fee survival almost 10 months, I have tried to get it for patients. That's not what the label offers at the moment. Sometimes it's cover most times it's not, but I would absolutely, if I'm thinking a patient is appropriate for a doublet, think about that regimen in patients. Well, you started out by saying that this treatment here is palliative intent. So keeping those nuances inside effects in mind is extremely important. Kevin, thanks so much for touching on some of the clinical pearls, especially with clarinetin use. What about that overlapping disease? That is where you have ESR1 and pick 3CA or AKT or P10 loss mutation. What are you prioritizing oral surge or pick 3CA inhibitor or even in that case, the disease was to progress, are you sequencing these options? I think this is a moment in time where we are right now. And if I have a patient, and I'm not able to get ESR1 plus a BEMA cyclid for these patients, then I would think about utilizing full vestorant and capybacere tip. One of the concerns is that patients with Wi-Fi 3.7S mutations may not be as responsive to full vestorant compared to what we see with the oral surge. There are data from Ember 3 in a small population of patients who had double mutation, but ESR1 and a pick 3CA mutation did really well with that combination. And so I think that also the other thing to mention that we might see later this year is the approval of Jared Destin plus Everabind. That also may be a good combination in these patients because there was benefit regardless of the presence or absence of pick 3CA mutations. And so that's how I'm thinking about it now. Maybe full vestorant and capybacere tip, but if I'm able to get a doublet of Ember 3.7S, that is a reasonable option. Kevin, you brought up Jared Destin. What we are seeing here with Lidera, this being tested in adjuvant setting. Let's see how it all plays out, but this is exciting. Kevin, how about that particular disease where you don't have any ESR or AKT pathway mutation? The choices here are, EverLimus combined with Examistine, or we should not forget chemotherapy, and then we also have data on TDXD based off DB06 for that particular patient population where we have low or ultra low or too positive disease. When I will say if I have a patient who does not have any targetable mutation, but still they had what appears to be endocrine-sensitive disease, endocrine therapy plus EverLimus is a good regimen. This is a regimen that I often utilize. Sometimes they give it along with full vestrine based upon the older pre-cog data, but if they don't have any ESR or mutation, Examistine and EverLimus is a good option. Just to go back to clinical purls, one of the initial issues with adoption of EverLimus was the stomatitis, same thing that I'm mentioning in terms of that role of exorance. Let's say we are past the point of endocrine sensitivity and we need to move along. If a patient has low volume disease, something that keeps eye to the end is still absolutely reasonable for patients. If I'm in a situation where I need more bang for my bach or I'm concerned about the pace of disease or patients are symptomatic or developing significant dysromatasticis, this is where for the patients who have ultra low or low disease, utilizing something like TDXD is really a standard of care based upon the destiny breast of six data. You know, a few things here. Well, let's not forget that's their mouth. Well, I should've touched up about that in a novel. Let's say here for EverLimus, this will also get important when we're using data, DXT. Kevin, you brought up the DBO6 study. TDXD here based off low and ultra low herchew, but then we also have other ADCs available. Sassetism ad, which gave us overall survival and again, chemoresistant disease. We also saw data DXT approval based off PFS, but that did not meet OS endpoint. How are you sequencing these available options? After ADC upfront, do you give chemo and then come back to ADC? How do you pick one over the other DTODXD or Sassetism ad? So such good questions and we face this in clinic. So when I will say that we did see data from San Antonio that Komosha very had presented looking with a CENTO 7. When frontline Sassetism app compared to chemotherapy did not improve progression freezer survival. There was this trend towards overall survival, but in terms of the primary endpoint, that was a negative study. And so if I had a patient as herchew zero, herchew zero disease, and I need to do chemotherapy, and I would give chemotherapy as a first line and then second line, I would think about a trope to ADC. That could be Sassetism ad, or could be DTODXD. You know, one of the things in interpreting the overall survival data from DTODXD is just that there was more crossover as opposed to when Sassetism was approved based upon tropics of two. We didn't have other ADCs at that time. So, you know, how interpretable those overall survival data can a little be a little harder with DTODXD. I think these drugs are really quite similar in terms of their efficacy. SG, 2 weeks on, will make off. All the patients lose their hair. Often, you know, 25 to 50% of times, patients need to use growth factors and we can see diarrhea. DatoDXD, once every three weeks. So, for some patients, that's a benefit. Utilizing that oral rinse, as you mentioned, for stomatitis, is very important. And then the other thing is ocular issues. It's recommended that patients do not wear contacts while they're getting this drug. The other thing that can be helpful is ice chips during the infusion to help prevent dermatitis. The rates of neutropenia are less with this drug. To answer your question about her to ultra low low disease, where they have a tumor that's progressed on TDXD, you know, the data of trop two ADCs after TDXDs, unfortunately, somewhat limited. And in these, you know, the activity somewhat limited, where it tends to be the first ADC is better than the second. And we have ongoing prospective studies based upon retrospective studies. It seems to be somewhat limited. I have actually shifted from giving ADC after ADC outside of a clinical trial. We have other options that we can think about. I may sequence an ADC after that, though I will also say sandwiching it or giving one after the other, um, data seem to be about the same. They do have concerns just given the resistance that we see. Though we dive into some of these side effects a bit more in detail in our talks check series. And we have covered Sastitusumab and data DXD. Kevin, would you go on to when you are encountering these side effects? How are you managing? You shared your clinical pearls, but are you reducing the dose? Are you going one week on one week off sort of thing for Sastitusumab or anything around data DXD as well, please? Yeah. So with Sassy, I, one of the main reasons I've needed to dose reduce has been fatigue. And the only way that patients, some patients are able to tolerate is bringing down the dose. And I do have to do that for some patients. If I have an elderly patient, and they're still not tolerating that, it's been a challenge to do two weeks on one week off. I have done every other week dosing. However, we really don't have data for that. We have a prospective study looking to answer this question. There's an ongoing study regarding that for data DXD, the one thing I was going to emphasize is the risk of stomatitis for general oncologists who have not had experience with this because I've seen this happen in the community is it just takes one patient with one really bad stomatitis experience to be forever concerned about utilizing this drug so that oral steroid rinse is really critical for prevention. And again, just to reiterate for Sassy, to the map, we're talking about neutropenia, diarrhea, fatigue, alopecia with data DXD, dry eyes, mucositis, stomatitis, again fatigue here, small risk of ILD, TDXD, we also have to keep things like nausea, fatigue, alopecia, and of course not common, but life threatening ILD on our radar. The only thing is that I also add is that neutropenia when I sit high in the growth factor support because we've seen bladder cancer mortality associated with it, which is unfortunate. Absolutely. I'll look at critical points. And again, when we're talking about growth factors, either short acting or long acting after that day eight of your treatment, Kevin, before we close, any final thoughts when it comes to metastatic space? I have one additional thing that I am commonly getting asked by colleagues is this question about a trope 2 ADC after another trope 2 ADC. And we have very limited data. There's some data from the phase one experience TROPEON 01, where there were a few patients who received Sassy and had some benefit, but most didn't. So I'm not commonly giving a trope 2 if somebody had another trope 2. And I'm especially not doing it if they had prior TDXD. I just don't think it's going to work. You know, I just want to say that sequencing piece here is where many of us are feeling like we're flying blindly or shooting in the dark. And we're buying these side effects. We have to be very mindful, especially when the treatment intent here is palliative. Kevin, thank you so much for breaking this all down and sharing your current treatment paradigm for metastatic hormone receptor positive breast cancer. We're all head to close things on our end. Let's do a quick recap. In today's episode, we Dr. Kevin Kalinsky, we focused on metastatic hormone receptor positive breast cancer space, where we divide the disease into two buckets. High risk recurrent relapse disease or denoblum metastatic disease. For high risk recurrent relapse, based off in novel 120 we have approval of in novelist where what we have seen is more than doubling of PFS and what we have also is OS benefit. 34 months versus 27 months. Then we talked about denoametastatic disease where the standard of care is endocrine therapy plus deciding on CDK46 inhibitor, the choice is a BEMO cyclib or ribo cyclib. We moved on to the importance of NGS. ESR1 mutation or PIXB-C or AKT or P10 loss mutation, checking is extremely important because there are clinical implications tied to this. Rahul, your thoughts here? Well, picking up with NGS, this is important even upfront because this is where a novel is said for that PIX3CA mutations are important. This is not a resistant mutation whereas ESR1 mutation as the disease progresses, we continue to see higher incidence of ESR1 mutation and I am also relying on liquid CTDNA when looking for ESR1 mutation. During the discussion we touched on endocrine resistant disease or options for a chemo, ADCs like TDXD based off DB06 for that low and ultra low HER2 positive disease. Here we have seen improved median progression free survival from 8.2 months to 13.3 months. Throughout this conversation we kept bringing back side effects and some clinical pros around managing these. Steroid Maltzwash to help with stomatitis with Evalymus with DatoDXT, other things to keep in mind were neutropenia when it comes to Sacitismab, ILD when it comes to TDXD. Here again, the treatment is with palliative intent so in our end we have to have that fine balance of improved survival and quality of life. Thanks for tuning in. Make sure to check out our other discussions for early stage hormone receptor positive, HER2 positive and triple negative breast cancer. We are The Oncology Brothers.