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Welcome to the Quick Consult podcast, brought to you by Metall. Before starting this podcast, please review the faculty information, disclosure statements, and learning objectives using the link in the episode description. To claim your CME credit, complete the evaluation using the link in the episode description. This podcast episode is a continuing education activity managed and accredited by Global Education Group in collaboration with MTA. This activity is supported by an independent medical education grant from Pfizer and Arvina. Welcome back to Metal CME podcast series, and in this episode we are going to be focusing on endocrine receptor positive HER2 negative metastatic breast cancer. I'm your host, Doctor Phil McElnay, and I'm here again with Doctor Seth Wander, and in our last episode, we explored the critical role of biomarkers, and today we're addressing, The question that follows, after CDK 46, what's next? A major point of development in this space. Doctor Wonder, thank you so much for joining us again. Oh, thank you, Doctor McIlmay, my pleasure. I appreciate the opportunity. After progression on CDK 46 inhibitors, oncologists often face uncertainty in sequencing. What framework do you use to guide these decisions? Yeah, this is an area of very active research and clinical development, and as we have been discussing over, uh, recent sessions, we've, we've really entered the era of personalized medicine here. The way that I would build this framework is to view it from two lenses. The first is a molecular genomic lens, what is the makeup of the tumor at the time of progression? We really need typically circular. tumor DNA assay after progression on a CDK 46 inhibitor to understand potential mechanisms of resistance and targets for some of these newer drugs. The second lens is, is really a practical clinical lens. Who is the patient? How old are they? What are their performance status? What is the state of their disease? How fast is it progressing? What are their laboratory parameters? And by putting these two things together, we can come come up with what we think is the best option or the best options, if there are multiple scenarios that would be reasonable for the patient. I'm being purposefully vague here because you can imagine a lot of different scenarios. You could have a scenario where you have a patient with no targetable biomarkers. You could have a scenario with a patient who has multiple biomarkers that lead to several different drug choices. You could have a patient who's We've got no significant medical comorbidities, totally normal labs, and no symptoms. You could have a patient who might be older, with limited functional status, or who has rapidly progressive disease with end organ visceral compromise, and everything in between. And so by putting those two spectrums together, we get a list of therapies that the patient's eligible for, and then we have to use the, the sort of traditional clinical metrics. To decide which among those choices is, is most reasonable. That's super helpful. A key part of that decision is the emergence of new endocrine strategies like oral ser and Botta. How do you see those fitting into treatmentsequencing compared to Current standards. We're in a very interesting moment right now, and I think it's going to be this brief kind of episode in time where we have in the US multiple next-gen oral anti-estrogens approved as a single agent, and we may see another, uh, with veeptogestrin, uh, from the Verit 2 study at some point. And, and this is great. It provides new therapeutic option for patients with ESR1 mutations, and as we were discussing a little bit previously, really the best patients who are candidates for this are ones who have a good prior duration of therapy on their first line endocrine and CDK inhibitor, and have maybe more indolent disease, patients where they're going to be, you know, sort of a good fit for using a single agent endocrine after a doublet in the first line. Now, in the future, I actually, I think it'll be a little bit more complex, but again, better for patients in that we're not going to use a lot of these drugs as single agents for a long time. We're currently seeing them under development as doublets and triplets with currently available CDK 46 PI3K pathway inhibitors, and with emerging next-generation CDK 42 and next-generation PI3K pathway. And so, we're not gonna have to worry quite as much about monotherapy being inadequate, because we're gonna have doublet reg. coming up in the near future. We're also not gonna have to worry as much about those patients with the dual mutants, the patients who are both PICC3CA and ESR1, because we're gonna have regimens that do both, right? That have a good ESR1 targeted next-gen anti-estrogen and have a good next-gen PI3K targeting agent. So, for right now, I would look at this as, as a transitional moment where these drugs are beginning to move into the clinic. As single agents, they are gonna be good options for a subset of patients, but we're soon gonna have the option of using In combination, which will expand the spectrum of patients who are going to be eligible to get them. And I hope that we can come to a point where the vast majority, if not all, but the vast majority of patients in the 2nd and 3rd line ER positive, HER2 negative metastatic space can access these next generation oral drugs, either as a single agent or in combination. Speak about some of the emerging data. Can you share some insights from some of the recent clinical trials, for example, Veritak 2. That are especially relevant for clinical practice. Yeah, Veritak 2, very interesting study using a novel protac, proteolysis targeting chimera. So, this is conceptually similar to the idea of an ER degrader, but it really supercharges that concept. So, it pulls the machinery of cellular degradation to the target protein, in this case, ER, and tags it for destruction, right, within the cell. The Veritak 2 study looked at a patient uh population who had had prior progression on a CDK. 46 inhibitor. These patients were randomized to get fulvestrant versus veeptigstrin, the first oral Protac, and the outcome looked similar to our experience with, for example, Eliestrin and immunestrin. We had um a steep drop in a proportion of these patients who really weren't sensitive to either endocrine agent. And then for the patients that had the ESR1 alteration, there was a separation between the curves, and an improvement from about 2 to 5+ months for these patients with the Protac as a single agent. Like many of the other oral anti-estrogens. This drug is very well-tolerated with minimal subjective toxicity. And in my experience, many of these newer drugs are actually better tolerated, for example, than aromatase inhibitors, uh, where you get a lot of hot flashes and joint pain and things like that. So, I think very interesting drug, very interesting study, an important potential new option for patients that may enter the landscape at some point in the near future. And again, looking to the middle distant future, what are we gonna learn about combinations with this drug? What sort of doublet regimens might emerge? That allow us to expand the spectrum of patients who, who might benefit. And the last thing I'll say about it is, with all these new anti-estrogens coming in, into practice, we don't know anything about sequencing those. So, what about using, for example, a CED and going to a protac? Can you regain some degree of activity by sequencing these types of drugs? We have no idea. This is a totally open question and a black box that we are just going to begin to start to look at once, once we have this in clinic. That really puts the latest data. Into context. We know that molecular resistance patterns, particularly ESR1 mutations, can complicate sequencing choices. How do you balance that molecular data with other patient-specific factors like the duration of their prior therapy, symptom burden, comorbidities when making a final decision? Yeah, and, and again, I think this is very patient-centric and a highly personalized choice. The way that I think of this in, in my own practice is, at the time of progression, we're getting all the genetic. Molecular information, and I'm thinking about what options are potentially on the table. So, for example, if they have ESR1, I'm thinking now about Eliestrin and imlinestrint. If they have a PICC-3CA pathway alteration, I'm thinking about alpeliib and Capivasertib. Of course, in, in our back pocket, we still have the ADC, right? TDXD, chemotherapy, fulvestrant, etc. If, if, if the patient has more indolent disease or minimal amount of symptoms and laboratory parameters are within acceptable ranges, I tend to prefer to use The sort of least toxic, easiest medication I can, that will limit the back and forth to the clinic, hopefully, all oral, etc. And as you move across the spectrum, and the patient, for example, has comorbidities like uncontrolled diabetes, that would limit my ability to use the PI3K inhibitor, or the patient has really symptomatic visceral disease, or doesn't have any actionable biomarkers, then I'm starting to lean more towards something like TDXD or Conventional chemotherapy that'll give me a quicker response, and will hopefully make the patient feel better, you know, faster. So, I, I think you have to balance these factors, but the important thing here is, you can't understand the tool kit that you have, if you don't have the updated DNA sequencing results. This really highlights to your point about ESR1, the importance of repeating the sequencing at the time you're making the clinical decision. And that's why we typically will send a Liquid assay. We can now get a turnaround time within about 1 to 2 weeks. We don't have to do an invasive procedure, and we get a good look at ESR1, at PI3K, at AKT, at P10, at tumor mutational burden, etc. Because things can change over time, right? Under pressure on different therapies, and that can impact what we can put on the table to then cross-check against the various clinical parameters that we were discussing. It's all about individualized medicine. At the end of the day now, isn't it, that brings me to my.