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My name is Mark Pegram. I'm a professor of medical oncology at the Stanford University School of Medicine in Palo Alto, California. I'm pleased to present this presentation entitled Differentiation of Emerging Endocrine therapies in Estrogen receptor-positive HER2 negative metastatic breast cancer based on mechanism of action and clinical role. Please keep in mind my disclosures of financial relationships within the past 24 months and take these into consideration as you listen to my remarks today. The learning objectives for this presentation are to differentiate emerging endocrine therapies and estrogen receptor-positive HER2 negative metastatic breast cancer based on mechanism of action and clinical role, to describe the mechanisms of novel endocrine therapies including proteolysis targeting estrogen receptor degraders, so-called protax. Contrast these therapies with traditional selective estrogen receptor-degrading agents and selective estrogen receptor modulating agents based upon efficacy and mechanism. And finally, evaluate how mechanistic differences influence therapy selection and endocrine resistant hormone receptor-positive HER2 negative metastatic breast cancer. As you can see from the summary slide timeline, the FDA has been quite busy over the past decade or so in this space with multiple new drug approvals, including the CDK46 inhibitors in the first line combined with uh aromatase inhibitors, uh, immunotherapy for um, uh, uh, uh, triple negative breast cancer. Uh, more targeted therapies targeting Etre and RT. Also trastuzumabroxan, uh, for HER2 low and ultra-low metastatic breast cancers that are hormone receptor positive, uh, data datapodumabdroican, uh, involliib plus fulvestrin palbociclib, Capivasertib, Eliestrin, stuzumab, gobotecan. And finally, um, just last week, there was a new FDA approval of immunnester shown in the lower right by the dotted red box that was approved on September 25th with the indication statement from the FDA and estrogen receptor antagonist indicated for treatment of adults with ER positive HER2 negative ESR1 mutated advanced or metastatic breast cancers with disease progression following at least one line of endocrine therapy. Uh, the companion diagnostic for that agent is the Garden 360 CTDNA assay. Doctor Gratischer at this year's ASCO presented a very nice, uh, summary of endocrine agents in development. As you can see, there's, uh, many oral surges that have been in development over the past years, including some not even shown on the slide that I actually worked on, including G1T4A, for example. Um, and in addition to the oral serts, there are also the protax and the CERNs and the circus. CERA stands for complete estrogen receptor antagonist. It's kind of, uh, I would describe it as midway between a CED and a SERM. It can both block ER binding to estradiol completely, and it also leads to at least some degradation. Meanwhile, CICA stands for selective estrogen receptor covalent antagonist by targeting A unique cystine residue, C530 within the ligand binding domain of the estrogen receptor. And uh that also blocks ER action as a transcription factor. Estrogen receptor gene mutations were first described by Suzanne Fuqua at San Antonio uh back in the early to mid 90s and published in Cancer Research in 1997. And what she described was one patient with advanced disease out of 30 samples tested that had a Y537N. ESR1 gene mutation. She postulated a model that describes this mutant as being constitutively activated as a transcription factor, even in the absence of estradiol. This also uh had a phenotype of being drug resistant uh against uh drugs like tamoxifen and aromatase inhibition, for example. Now, uh, the SED drugs, uh, particularly the oral bioavailable SEDs, uh, an example is shown on the right, and I've chosen Camiestrin simply because we have both X-ray crystal structure available for this drug, as, as well as Western blood analysis and cell-proliferation essays, uh, published in a paper by Scott. But I could have chosen any one of the oral surgeons to describe this mechanism of action, so there's no specialty about Cammiestrin in this case. You can see by the Western blood analysis at the bottom center of the slide, that compared to fulvestrant, there's nice degradation of the estrogen receptor protein over time, um, following exposure to this oral ser cabaz estrin. And also this correlates with a decrease in cell proliferation. Important to note out that uh this oral ser as well as others, blocks cell proliferation of both the wild type estrogen receptor as well as the mutant estrogen receptor. Also note that oral ser mechanism of action involves ER protein binding resulting in misfolding of the estrogen receptor protein, resulting in polyubiquitation. And subsequent proteasome degradation. And this is important because we're gonna talk about that mechanism with the protax shortly as well. Since the original publication by Fuqua and all, uh, there have been over 30 different ESR1 mutations, uh, discovered. Uh, there's a summary in the middle of the slide showing some of the locations of these, uh, uh, ESR1 gene mutations. They do tend to cluster in certain hotspot regions, including the ligand binding domain, for example. In Fuqua's original paper, the incidence of ESR1 mutation and newly diagnosed early-stage breast cancer was low, less than 1%. And so for the better part of a decade, this target was largely ignored in the research community because it was thought to be so infrequent that uh no sponsor would probably take on a project designing a new whole drug class to target such a rare mutation. But years later, it turned out that in metastatic breast cancer, the incidence of ESR1 gene mutation increases dramatically. 5% by the time of first recurrence. And uh by second line, it's up to a third of patients have ESR1 gene mutations. And third line up to 40% as shown on the uh graphic on the lower right-hand side of the slide. Again, the cartoon on the left shows the mechanism of action of these mutant receptors being constitutively activated and activating ER in um these mutant cell lines which causes increase in proliferation. And indeed activates uh metastatic cascades in terms of gene expression profiles. Next, I'll show you the phase 3 Emerald clinical trial, which was the first oralE drug to lead to an FDA approval, that is Eliestrant. The inclusion criteria included men or women with metastatic breast cancer who were hormone receptor positive and HER2 negative, who had progressed or relapsed on or after 1 to 2 lines of endocrine therapy for advanced disease, one of which was given in combination with the CDK 46 inhibitor. Up to one line of prior chemotherapy for advanced disease was also allowed. And the uh ECOG performance status had to be uh very good to excellent. Patients were randomized 1 to 1 to LSestrin 400 mg a day, or investigators' choice of standard endocrine therapy, fulvestrant or any one of the three aromatase inhibitors. The, uh, two primary endpoints were PFS in all patients and PFS in the ESR1 mutant subpopulation. Key baseline characteristics were balanced between the two randomization arms, visceral metastasis, about 70% prior adjuvant therapy in over half. Prior aromatase inhibition in over 80% and prior fulvestrin in about 25 to 30%. The Enbrel trial, uh, landmark analysis of PFS in patients with detectable ESRN1 mutations met its primary endpoint with statistical confidence. This, uh, Kanmeyer plot shows the hazard ratio of 0.5 with a P value of 0.0005, indicating superiority of LSestrin over fulvestrant as the control in this particular illustration. Um, note the shape of this curve. Almost a third of patients drop out at the first restaging interval at 2 months. And we need to better understand the resistance mechanisms in this patient population. Apparently, it's not something so simple as which ESR1 mutation they have because that data has been available to sponsors for months or even longer. Uh, so it, it has to be something more complex that's under active investigation and biomarker campaigns. And this and other trials that are ongoing. So, we need to be able to identify those patients to exclude them from future uh SERD considerations since they do not respond. But the remaining patients clearly have a much better outcome in terms of time to events analysis. Note that there are unique side, side effects associated with this particular oral CERD and particular nausea. Which can happen in about a third of patients compared to almost 20% in the control arm. Uh, vomiting as well. Consequently, anti-emetic medication, co-medication is recommended on a PRN basis when you prescribe this agent. There can also be some anorexia in a fraction of patients, uh, and that's a little bit more compared to the fulvestrit control arm. In the future, there are ongoing phase 1B and two, combination studies that are underway combining LS Erin. With not only the CDK 46 inhibitors, but also uh everolimus, the MTOR inhibitor. And stay tuned for future updates with these combinations. It may be possible to integrate this agent with other drug combinations in future uh studies. Hopefully, it's leading to new drug approvals in the future. Next, I'd like to talk to you about the newest oral er to be approved by the FDA last week, immunneestran. This is the pivotal