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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 is a continuing education activity managed and accredited by Affinity CE in collaboration with Metal. This activity is supported by an independent medical education grant from Pfizer. Hello and welcome to the HER2 positive metastatic breast cancer unfiltered episode of the podcast. That translates to cutting edge evidence into clinical practice. I'm your host, Doctor Phil McElnay, and today we're incredibly honored to have a leading expert in oncology with us, Professor Mark Pegram. We'll be diving deep into one of the most interesting and evolving areas in metastatic breast cancer, optimizing maintenance therapy. We know from recent and emerging data that uh healthcare professionals are really interested in this space about de-escalating therapy, integrating endocrine agents, and our goal today is to provide clear practical guidance to help close some of those gaps for you. Professor Pegram, thank you so much for joining us. Well, it's, uh, my great pleasure to have an opportunity to work with you again. We've done some programs before together and it's always been a Very interesting, challenging, and, and fun for us, actually. So it's a, it's a pleasure to be back. Thank you so much for inviting me. Uh, that's brilliant to hear. Let's start with the evolution of maintenance therapy. How has the evidence of HER2 positive metastatic breast cancer maintenance evolved from the landmark Cleopatra trial to today? Well, it's interesting you call it evolved. The problem, Phil, is that for the longest time it didn't evolve. The Cleopatra trial. It was first published on the same day it was presented at uh San Antonio Breast Cancer Symposium in 2011. And so for over a decade, it's been the standard of care for first-line HER2 positive metastatic breast cancer, and there have been really no serious challenges until this past San Antonio 2024 and again, ASCO 2025. Finally, we have a threat to the reign of uh Cleopatra, if you will. The Cleopatra trial, of course, showed a significant improvement in progression-free survival for patients. Taking pertuzumab along with trastuzumab and Ataxane compared with the placebo and trastuzumab and docetaxel. The median PFS was about 18.5 months for the pertuzumab group versus 12.4 months in the control group, and the overall survival was improved by a significant amount, also about 56.5 months compared to 40.8 months. Finally, uh, after all the years of treating patients with Cleopatra-like regimens, in San Antonio 2024, the Patina trial. was uh presented for the first time, uh, as a late-breaking abstract indeed. And it showed that the addition of CDK46 inhibition to endocrine therapy plus dual antibody therapy for so-called triple positive disease, that is HER2 positive and ER or PR positive. You know, that, that was a positive trial, and I'll tell you about the details in a minute. And also, the Destiny Breastto 9 trial was presented at ASCO this year, which looked at uh TDXD plus pertuzumab versus the Cleopatra regimen control arm. The TXD arm was far superior. I'll start with the Destiny Bresto 9 clinical trial since it's the most recently reported. It's a global randomized open label phase 3 study enrolling. 1160 patients, first line HER2 positive metastatic disease. They're randomized to one of three arms, trastuzumab drug can plus a placebo, TDXD plus pertuzumab, or the Cleopatra regimen as a control arm. The primary endpoint was progressive free survival by a blinded independent central review. The trial demonstrated that TDXD plus pertuzumab achieved a median PFS of 40.7 months versus 26.9. In the control arm, so that's a significant difference. Also, the combination showed an unprecedented objective response rate of 85% compared to about 78, 79% on the control arm. The complete response rate was also impressive, 15.1%. So, these are extraordinary results. TDXD plus placebo arm was not yet presented cause there were insufficient events uh in that um comparison to be uh Analyzed yet, so stay tuned for the third arm comparison in the not too distant future, I'm sure. At the time of data cutoff, the overall survival data was not mature, only about 16% maturity of the data. But there was a favorable trend, which is interesting. And PFS 2 was significantly prolonged. And sometimes that can foreshadow ultimate OS results in the future. So hopefully that That'll be the case for this trial. Of course, one must watch out for TXD associated toxicities. Uh, TDXD has been reclassified as a highly emeogenic agent, and it requires a three-drug anti-emetic, uh, prophylactic regimen. The Destiny Brusso9 trial is currently under FDA review with a priority review status granted in 2025, and the decision is anticipated. Probably by the first quarter of 2026, and uh NCCN guidelines acknowledgement of Destiny Brussoine is still pending. And I think uh we're gonna talk about the Pinna trial in much more detail in the future questions in our discussions today. So I'll save the analysis of that for the next few minutes. Let's lead into the next question, which is about de-escalation. What does maintenance de-escalation mean in practice and should Just consider it. So, maintenance de-escalation is a term that's used to describe what I would actually call induction followed by maintenance. For example, in the case of the Cleopatra regimen, you start off with a chemotherapy plus dual antibody regimen, but eventually, patients either develop chronic toxicities from the chemotherapeutic component of the regimen, or they achieve Give some maximal response, and after more cycles, there's no further response. So one wonders, you know, do you really need to continue that induction chemotherapy component forever? The answer is no. What clinicians do is they drop the cytotoxic chemotherapy component, and then continue on with the dual antibodies as a maintenance strategy. And so now, there are clinical trials like the Pinna trial that we'll talk about. That is a maintenance strategy that for triple positive patients, those patients that are both hormone receptor positive and HER2 positive, they can take dual antibodies plus endocrine therapy, plus a CDK 46 inhibitor. So, uh, that'll, you know, that's a really interesting twist, and it's an example of a recent positive randomized phase 3 trial of a so-called induction maintenance strategy. And uh the same is probably gonna be true following this breasto 9 strategy. With trastuzumab, droxican, and pertuzumab, that can also be considered kind of um, uh, an induction regimen. Cause you can't take TDXD uh forever. There are cumulative toxicities that eventually catch up and patients just get, uh, you know, tired out from, from that regimen. And eventually, you, you must discontinue the TDXD component, and then switch to, uh, Uh, some sort of a maintenance strategy, uh, whether that be dual antibodies or maybe in the future even dual antibodies, plus CDK 46 inhibition for patients who are also a steroid receptor positive. And that nuance is quite. Important for those long-term responders, what factors guide your decisions on how long to continue HER2 targeted maintenance? Great question. You know, there are a, a small fraction of patients with HER2 positive metastatic disease that are so-called exceptional. Responders, you know, usually having a complete clinical response in all metastasis by resist criteria. And for those patients we've all had the experience that upon cessation of all therapy, including all the HER2 targeted therapy, those patients can have a normal lifespan apparently and are You know, for all intents and purposes, they appear to be cured, and that's really extraordinary. There aren't enough of these patients, unfortunately. It's a small fraction, but they're out there, and it's important to identify those patients. Cause that's another opportunity for quote unquote, de-escalation. In this case, de-escalation would mean drug holiday altogether. You could stop everything. The hard part, Bill, is trying to talk patients into stopping treatment, because patients are scared, some are superstitious, they get into the habit of coming into the clinic for their therapy. It becomes kind of a social outing. They often meet other friends in the waiting area and Uh, I've heard patients that go out to lunch or dinner together on their treatment days, or go shopping together, etc. So it becomes like a pattern. Patients who are superstitious don't want to break that pattern. They, they feel like if they stop all treatment, maybe the cancer will come back. So it's a discussion. And I start Having those discussions for patients who have been in complete remission or near complete remission after, you know, 2 or 3 years, you can start having that discussion. I've probably not met anybody who stopped much before 4 or 5 years, to be honest, because it's hard to talk them into it. But that opportunity is out there, and so clinicians should be mindful of that and be on the lookout for it. Let's talk real world. What are the biggest challenges? That healthcare professionals face in translating trial results into their real-world clinical practice. Absolutely. I would say the biggest challenge lately has been the pace of new data in the treatment of breast cancer, not just HER2 positive.