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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 back to the HER2 metastatic breast cancer unfiltered podcast series. We're planning to translate some cutting edge evidence into clinical practice. I'm your host, Doctor Phil McElnay, and in our last episode we were joined by Professor Mark Pegram for a fantastic discussion. On the evolution of maintenance therapy and de-escalation, and today we are thrilled to have him back again to continue that conversation. We'll be focusing on the important and complex subset of patients with dual positive or HER2 positive, and hormone receptor positive metastatic breast cancer. We know that colleagues are a little bit uncertain about the role of endocrine therapy in this setting, and our goal is to provide Clarity on integrating these crucial changes. Professor Pegram, welcome back. Well, it's so nice to be with you again, Phil. Uh, thank you for inviting me. I'd love to dive in with the biological rationale in mind. Could you summarize the key takeaways from trials like Prota, Latina, moniker that inform how we integrate endocrine therapy? Great question. Uh, I suppose. We should look back into history to begin the answer to this question and talk a little bit about crosstalk between estrogen receptor and HER2. Doctor Richard Petris from UCLA was the first to describe crosstalk between HER2 and estrogen receptor in the literature back in 1994. And I remember back in those days, UCLA even put out a press release to describe the synergy between anti-estrogens. And anti-HER2 therapies. And it was really exciting to us, and it was validated in other laboratories, uh, as well, ultimately. Um, and nobody paid any mind to it. Nobody paid any attention to it for the next better part of a decade, I would say. Uh, until finally, around about 2009, 2010, uh, we participated in the uh letrozole lapatinib. randomized clinical trial, and for the first time, got an FDA approval of that regimen based on a phase 3 clinical trial study that we published in the, in the JCO back in those days. So, it just kind of underscores the length of time it takes to get from the bench to the bedside. It's not always free-flowing and spontaneous and automatic. There was a lot of skepticism and, um, you know, criticism, etc. over the years. And Until finally, we, we were able to convince somebody to do a trial, and it turned out to be positive, so we were very pleased about that. So let's move on to pertain and Pertina and moniker, more modern studies since that time. Pertain is a randomized open label multi-center phase two study, randomized 1 to 1 to receive pertuzumab with trastuzumab and an AI or trastuzumab and an AI alone. So it's a, it's a pertuzumab question with endocrine therapy. The primary endpoint was PFS. In the final analysis, with over six years of median follow-up, the pertuzumab randomized patients had an improved median PFS compared to trastuzumab and AI alone. It was up to about 20.6 months versus 15.8 months. So, you know, not as much as you would expect from a Cleopatra-like induction regimen for these patients. But for some patients, particularly those who are elderly, multiple comorbidities, contraindications to chemo, or, or who refuse to take chemotherapy, there are some patients who simply will not take chemo in our clinics. And consequently, this is a non-chemo option that is available based on the strength of the pertain trial. So it's nice to have options for patients who may be challenged from taking chemotherapy regimens. Betina is a very exciting trial that just presented at San Antonio last year in the late breaking abstract. It showed that uh by adding a CDK46 inhibitor, palbociclib, to standard anti-HER2 therapy plus endocrine therapy as maintenance following a Cleopatra induction regimen, significantly improves, improved progression-free survival with a median PFS of 44.3 months compared to 29.9 months in the anti-HER2 therapy and an endocrine therapy. Alone control arm, an extension of over 15 months. So that's based on the pre-clinical paper published by Sean Gold and colleagues from Dana-Farber, published in Cancer Cell back in 2016. So again, almost 10 years ago, the laboratory discovery research was published, and we finally have a phase 3 trials proving that that synergy between CDK 46 inhibitors and HER2 targeted therapy is also a significant improvement. And finally, the moniker trial was a phase 2 trial evaluating a bemicycllib combined with trastuzumab with or without fulvestran versus standard chemotherapy plus trastuzumab in women with a hormone receptor positive, HER2 positive, advanced breast cancer, and at least 2 prior HHER2 targeted therapies. So this is not a first-line trial. Uh, the trial showed that the combination of abemiiclib, trastuzumab, and fulvestrin significantly improved PFS compared to chemotherapy plus trastuzumab control, with a median PFS of about 8.3 months versus about 5.7 months in the control arm. There was a numerical improvement in overall survival as well, with the medians of 31.1 months in the Abemicycl arm versus 20.7 months in the control arm. The safety profile included common side effects of abemicycllib as expected, cytopenias, diarrhea, some fatigue, etc. but um no new safety signals with this combination. And uh Moniker set the stage for the integration of CDK 46 inhibition, along with her two targets. Therapy that now we have the phase 3 Patina trial to support. You mentioned something really important, which is endocrine receptor and HER2 pathways and their crosstalk. Why is that interaction important in metastatic disease? It's a therapeutic opportunity. It really boils down to just that, you know, when you have synergy between two active therapeutic interventions, you know, endocrine therapy and HER2 targeted therapy, then um, You know, the, the outcomes are far superior when you can exploit targeting both pathways instead of either one alone. Moreover, HER2 and downstream signaling resulting from constitutive activation of HER2 when it's overexpressed, leads to endocrine resistance. And by blocking HER2 with a HER2 targeting drugs, you can block some of the endocrine resistance. So that's probably the ultimate mechanism or one of the ultimate mechanisms of the synergy is overcoming endocrine resistance that's actually caused by HER2 positive breast cancer. And so it's a fascinating interaction, and one that we can clinically exploit, and turns out to be an important interaction. The converse, you could argue, is also true in neoadjuvant studies. Hormone receptor positive HER2 positive patients. have a lower pathologic complete response rate to neoadjuvant therapies compared to patients that are hormone receptor negative and HER2 positive. So that suggests that there may be some component of resistance to HER2 targeted therapy in patients who are also ER positive. So it's kind of a yin yang thing. There's, there's overcoming resistance in both directions, if you will, with the combination of the dual combination of HER2 and endocrine receptor targeted therapy. So we've chatted about the biology, we've chatted about some of the latest clinical trials. Let's talk practicalities. How do you decide between using endocrine therapy alone, adding a CDK 46 inhibitor, or layering these with the ongoing HER2 targeted therapies? Well, you know, right now, as, as we're here in the October of 2025, the Betina clinical trial is currently under regulatory review, um, but it's not yet, uh, won FDA approval. In the US and also the Pinna regimen has not been broadly incorporated into NCCN guidelines, but it's anticipated to be considered following regulatory review and approval in the future. So right now in the US this is more challenging because it is difficult to get insurance coverage for the CDK46 inhibitor. So from a practical standpoint, it's more of a waiting game for the regulatory approval. This is true in Europe as well. So, uh, You know, that's, that's a frustrating thing. And, and sometimes for patients that are maybe high enough risk, Um, we will appeal to insurance companies, and sometimes we win those appeals in peer to peer discussions with the physicians who work at the insurance companies. We can use abstract data sometimes to support integration of a new promising therapy, even before regulatory approval or guidelines accepted. So that, that's where we stand right now from a practical point of view. After Patina becomes available, presumably. In the, in the not too distant future, then it's gonna have to go up against the likes of Destiny Breast 9, which showed superiority of trastuzumabdoxican plus pertuzumab, compared to a Cleopatra-like uh regimen as induction for a first-line HER2 positive metastatic breast cancer. So in that case, it's gonna be a balanced discussion between the two with uh patients, if they're hormone receptor positive. If they're hormone receptor negative, then only The Destiny breast 9 data would apply. Uh, but for those patients that are ER positive and HER2 positive, you could discuss both, and the expectations and