All right, I am going to stay up on the stage as I'm going to be presenting the second patient who is a, um, a postmenopausal woman with a newly metastatic ER positive breast cancer. Um, And so, you know, I, I assigned myself this task with the hope that I was gonna learn something, um, and, and I started with this and, and we have a lot of treatment options for this patient population and, and when I think to 15 years ago when I started fellowship, um, almost 16, like we didn't have half of these options and. I think we're moving in the right direction, but, you know, the next question is, is how do we sequence these options? Well, There's some interesting trials that got presented last month, and let's try to go through them and, and maybe we can think about it. So, in the frontline setting, there were two trials that were discussed. There was the Ombre trial and Serena 6. So, in the Ombre trial, we have a trial that did a randomized phase 3 study comparing mono chemotherapy versus abemicycllib and endocrine therapy in this patient population with a high visceral tumor burden. And so this was an ER positive, HER2 positive advanced breast cancer with no prior therapy in the advanced setting, um, but with a high tumor burden, they, it, um, defined that with two or more visceral sites, one visceral site with 3 lesions, or one visceral site with a high LDH. They did look at patients with primary endocrine, um, Uh, resistance, and they looked at a planned analysis of looking at capecitabine versus paclitaxel. There was a randomization of 180 patients to chemotherapy, of physician's choice versus endocrine therapy. The physicians were allowed to choose between oral capecitabine versus Paclitaxel. Interestingly, after finishing a course of chemotherapy, they were able to move the patients then on to maintenance of bemicycllib and endocrine therapy. The endocrine therapy was being given with either a non-steroidal aromatase inhibitor or fulvestrant in combination with bemicyclib. The exploratory endpoint also included checking a CTC count, um, at baseline and after 3 weeks of therapy. The primary endpoint of this trial was looking at PFS. And so, interestingly, we found that the patients receiving endocrine therapy did better than those on standard of care therapy, with almost a doubling of the, uh, a doubling of the PFS from 7 to almost 14 months in those patients that received combination therapy with a hazard ratio of 0.67. Um, and I think, you know, and the other interesting point that I'd like to make here is that patients were able to be enrolled with an ECOG status between 0 to 2. And so this was actually a pretty symptomatic group of patients, most likely from disease or from comorbidities. And I think this is yet another piece of evidence that in this population, we should be using endocrine therapy and not chemotherapy. In looking at the CTC CTC count during therapy, they noticed that the patients that received endocrine therapy, 52% of these patients, um, went down in their CTC count to less than 5 versus only 38% in patients, um, that received chemotherapy. And there's a separate question here of how do we use CTC in the future to help us make a decision on how long to Stay on therapy. Could we have used this information to understand how long these patients were going to stay on chemotherapy? Patients on the Paclitaxel arm were on for about 4 months. For the patients that were on the capecitabine arm, they were on for about 6 months. And could the CTC have even helped us decide how long they need to stay on, on chemotherapy? Or could we have used that to help us predict, um, Uh, progression in the future, I think there's still a lot of research to be done here. The second study in this setting was the Serena 6 study. This is the updated results and exploratory analysis of the ESR1 mutation circulating tumor DNA dynamics from Serena 6 phase 3 study of Camizesterran with the CD46K inhibitor for those patients with an emerging ESR1 mutation during their frontline endocrine therapy. So as a reminder, these were patients with an ER positive, HER2 positive advanced breast cancer. They were already receiving their endocrine therapy with a CD46K inhibitor for at least 6 months. These patients were then enrolled if they had an ESR1 mutation that was detected in the DNA and they had no progression of disease seen on CT scan. 315 patients were then randomized to either continue therapy with placebo or switch to camazestrin with continuing their prior CD46K inhibitor with placebo, with treatment that was Continued until disease progression, toxicity, patient withdrawal, or death. And along with this, CTC DNA samples were continuing to be taken during cycles 12, and 3, and then in alternating cycles. And so what we found is that the switch to Camazestrin with a CD46K inhibitor prolonged the time to progression, as well as the time to first subsequent therapy with a progression-free survival that increased from 9.2 months to 16.6 months. Um, And so this was the first emerging evidence that maybe in looking at the CTDNA while a patient is on their adjuvant therapy, or sorry, their first-line therapy for advanced disease, that maybe a switch should be made in their therapy depending on their, um, their CTDNA results. I think what I found most interesting about this trial was the PFS2 data. So this is for patients after they've progressed on their therapy with Camizestrin or with continuing their AI and CD46K inhibitor, when those patients Progressed and went on to their second line therapy, there seemed to be a continuation of the effect of the Camizestrin during their second line therapy, and PFS2 was also prolonged in this group, 19.4 months versus 25.7 months. And they also noticed that in this group, there was a prolonged time to chemotherapy with an early switch, um, to chemotherapy in those patients in the, um, and, uh, non-camazester arm 18 months versus 22 months. In the correlative studies that were done in this trial, they also noticed that the ESR1 allele frequency was reduced in those patients receiving camazestrin. And I do wonder if it is in this reduction in the allele frequency that has led to the PFS2 being prolonged, um, in this patient population. The overall survival data is still immature. We're still waiting for that. I'll be very interested to see what that shows. But right now, there's some evidence that camazestrin with the CD46K inhibitor appears to be a future treatment option for those patients with an early ESR1 mutation without progression of disease. So, in thinking about second-line therapy, there were actually quite a few trials that were presented. First, we'll look at alpeliib with fulvestrant for patients with the PICC3CA mutated hormone positive HER2 negative advanced breast cancer after progression on a CD46K inhibitor. This was a phase 3 randomized double-blind placebo-controlled trial. Again, this was a group of patients with hormone positive HER2 negative breast cancer with the known PICC3CA mutation. Um, these patients had to have measurable disease. They could have had one line of chemotherapy in the advanced setting. They had to have tumor available to be sent to a central laboratory for confirmation testing. Um, patients were receiving Alpelicid 300 mg along with fulvestrant, and the control arm was placebo plus fulvestrant. And I just want to take a moment to recognize that we know now from the maintained trial that this may not have been the optimal control group arm. We know that patients benefit from a second-line CD46K inhibitor, um, after progressing on a CD46K inhibitor. And so, we can start to ask questions whether or not this was the appropriate control setting. But at the time this trial was written, that prob that result probably wasn't back yet. Also interesting about this trial is that there was, uh, a loud crossover from the placebo arm to the alpeliib arm, um, at the time of progression. The primary endpoint of this trial was progression-free survival, with secondary endpoints, including what you can see here. 71% of these patients had liver metastasis. 12% of patients in the opulsive arm did receive prior chemotherapy, while only 18% of patients in the fulvestriran arm had received chemotherapy. Um, and 11% of the patients in both arms had progressed within 6 months of starting their endocrine therapy with the CD46K inhibitors. So, a little bit of a sicker group with some, um, uh, endocrine resistance of note. Um, And for the sake of time today, I'm going to go straight to the overall survival data. And this did show a median overall survival benefit that increased from 23.8 months to 29.5 months in the alpeliib plus fulvest and arm with a hazard ratio of 0.64. Dose reductions were required in 56% of the patients and dose reduction dose interruptions were required in 70% of the patients receiving alpeliib. However, they noted that most of the discontinuations were secondary to progression of disease, not toxicity, and these patients were able to restart therapy and stay on treatment, um, and not discontinue alpeliib. Um, and toxicity of alpellisib is, uh, the grade 3 toxicity from alpellisib is known to be hyperglycemia and rash. Um, And so, a really nice second line option for our patients with a PICC3CA mutation. Um, the next trial to look at is the Victoria 1 trial. This is gegetatoliib, a multi-target PICC3 AKT MTOR inhibitor plus fulvestrant with or without palbociclib in the second-line setting for patients with hormone-positive, HER2 negative. P PICC3CA wild type advanced breast cancer. So, again, the previous trial, um, with alpeliib was PICC3CA mutated. This is PICC3CA wild type. And so, um, Again, this is second line therapy. This looked at a triplet of geattoliib, palbociclib, and fulvestrin had a second arm for patients, uh, receiving geattoliib and fulvestrin. And we know that in the triplet arm, the median Regression-free survival was 9.3 months versus the doublet therapy, which is 7.4 months. And in this trial, what was presented last month with some additional subgroup analysis, expanded safety and some initial patient reported outcomes. Um, But what I thought was interesting in this first, in this first slide was they looked at progression-free survival depending on their response to their frontline therapy. So when they separated out those patients with, um, Really hormone, uh, sensitive disease, those patients who's, um, who spent more than 24 months on endocrine therapy and a CD46K inhibitor, their improvement in progression-free survival when receiving triplet therapy with geattoliib, palbociclib, and fulvestrant went from 2 months to 12.4 months. And in the, basically all come Population, um, that is where the progression-free survival benefit only increased from 1.9 months to 9.9 months. Um, and in the patients who had received the doublet therapy with getatoliib with fulvestrant, we again see an improvement in the progression-free survival with the doublet therapy, but maybe not as much as we saw with the triplet therapy. Interestingly, this trial did include patients with bone only disease, which is uncommon for many trials that we see. And we did see an improvement in progression-free survival in the triplet arm, they're, uh, still looking to see what their PFS is. They have not reached that yet, um, as well as in the, uh, doublet arm. So there's still a lot of information, um, that we're still waiting to see from this trial. The next trial that we'll talk about now is the EMRR 3 trial. This is looking at mluneestran with or without abemicyclib for patients with advanced breast cancer. Um, OK. Um, again, this is a patient population with advanced breast cancer that patients were allowed to be pre or postmenopausal on this trial. Patients can have had only prior endocrine therapy in the adjuvant setting with recurrence within 12 months of completion of their AI plus or minus the CD46K inhibitor. They could have received, um, one line of therapy in the advanced setting, um, with progression on their aromatase inhibitor plus or minuses CD46K inhibitor, but no other lines of therapy. So as you can see, they did need to stratify based off of their, um, previous use of A CD46K inhibitor. They looked at whether or not patients had visceral disease. Um, and there were three arms to this study. Patients either received immunneestran, single agent, they either immunneri, uh, with a bemacyclib or standard of care, and standard of care was single agent fulvestrin or exemesta. The primary endpoints of this trial looked at PFS when comparing immunneestrant to the standard of care arm with an ESR mutation, lunesran to standard of care in the all comer population, and immunestrant to immunnerin and a bemicyclib in the all comer population. In looking at the primary endpoint of PFS when comparing immunestrin to standard of care with an ESR1 mutation, we do see an improvement in the PFS from 3.8 months to 5.5 months with imluestrin as a single agent. What's interesting is that the overall, the interim overall survival, now, the maturity of this data is only 50%. In this patient population with an ESSR 1 mutation, the overall survival benefit is almost 10 months. How did we go from under 2 months? To almost 10 months is the question. And it makes you wonder what is, what is happening with the oral surges beyond the, the, the, the completion of therapy after they progressed. What is the continued response on the tumor after they've progressed on the drug? I think this is another trial that we are seeing that these oral surges have something else to them. The primary endpoint of uh PFS in comparing imlunestrin to abemicyclib, um, And imlunestrin, we also see an improvement in progression-free survival from 5.5 months to 10.9 months. There was also an improvement in PFS in patients that were previously treated with a CD46K inhibitor. They were also able to show that there was improvement in PFS. in patients with or without an ESR1 mutation, with or without a PICC3CA mutation, and they were able to show an improvement in PFS in patients that harbored both an ESR-1 and PICC3CA mutation. Secondary end point of looking at overall survival when comparing lusran versus the doublet therapy, still not mature, maybe we're, uh, headed towards imluneri plus a bemicycli looking a little bit better. But these results are starting to show that imlinerin has a meaningful, um, improvement in overall survival for patients with an ER ESR1 mutation, but also maybe in combination with the CD46K inhibitor, and maybe the ESR1 mutation. Doesn't matter anymore. I'm getting confused. OK. So, the next trial is the Elevate trial. This is Eliestrin in combination with everolimus or a bemicyclib in this population. This is a phase 2 study, open label umbrella trial. And so in this trial, women pre-menopausal or postmenopausal, or men, ER positive, HER2 negative, 1 to 2 prior lines of endocrine therapy were allowed. Prior fulvestrant was allowed, endocrine resistance was allowed. Um, but no prior chemotherapy was allowed. And these patients needed to have basically measurable disease. And the elevatete phase two trial, uh, dosing depended on the Elevate phase 1B trial and the Electra trial, where they looked at Eliestrin, uh, dosing, uh, dose. Ranges from 86 to 345 mg, combined with the drugs that you see here, we're going to be talking about everolimus, and then from the Electra trial, Eliestran with abemicyclib. They chose everolimus at 7.5 mg to help reduce toxicity. They chose abemicyclib at its full dose. And looking at the baseline care. Come on, you can do it. There we go. Um, in looking at the combination of Eliestrin with everolimus, we noticed that there were 72 patients with visceral disease. We saw that there were 20% of patients with primary endocrine resistance. All of these patients had a history of a CD46K inhibitor, and fulvestrit was used in 50% of these patients. And the PFS in In the all, in all of these patients was about 8.3%. And when looking at patients with visceral disease, no prior fulvestrin, no prior, uh, endocrine resistance, and ESR1 mutation or not, PIC3CA mutation or not, the PFS is pretty much maintained. And this was similar to what we see, we, we saw in the EMR 3 trial with imlunestrin and seeing that there was no change in PFS, um, depending on whether or not the patient had an ESR1 mutation or not, or a PIC3CA mutation. And looking at the combination with Eliestrin and a bemicyclib, again, 92% of these patients had visceral metastasis, 15% of patients had primary endocrine resistance. Um, only 50% of these patients were exposed to a prior CD46K inhibitor, and 30% of these patients had had fulvestrin. The PFS here was a little bit higher at 14.3%. Of note, the maturity has not been reached for PFS for looking at the genomic subgroups, the ESR1 population, the PICC3CA mutation, or exposure to a CD46K inhibitor. And I hope to see those results in the future. Um, And so with this study, Elevate, along with Ember 3, we can start to look towards oral steroids being used in combination with targeted therapy in the second line, or, um, or even in the, uh, frontline setting with an ESR1 mutation, um, from the Serena 6 data. In the, this last study, the Capitello 291 study, here, we had an exploratory CT CTDNA analysis that was discussed at San Antonio last month. Um, the results of this trial were initially published in 2023 in New England Journal of Medicine, demonstrating median progression-free survival that was 7.2 months in the cap ofvierative fulvestrant arm compared to 3.6 months in the placebo, uh, fulvestrant group. Um, and that analysis showed the tissue analysis that the AKT pathway altered population. Um, also benefited more from Kapaviseratib, um, than Fulvestrin, uh, as a single agent. And so, here, uh, the garden infinity assay was used on 708 patients. Unfortunately, 50 of these patients, they were not able to detect the CTDNA. The remainder went on, uh, to CTDNA. And, uh, CT DNA analysis, they found the P PIC 3CA AKTP10 alteration in 279 of these patients. There was co-occurring ESR1 mutations found in 149 of these patients. Um, and what is interesting that I'll, I'll just make a note of also is that in the tissue testing, um, that was previously reported, 289 patients had PICC3CA AKT P10 alterations. And so there did seem to be a slight discordance. And when they compared the tissue Testing to the CTDNA analysis, they noted that 10% of the pathway alterations were only found in CTDNA analysis. 11% of the pathway alterations were only found in the tissue analysis. And there were some patients with no ability to detect CTDNA and maybe this is from decreased shedding by the tumor. In looking at the summary of the PFS data, depending on the CTDNA alterations, it seemed that it, for the most part, most patients did benefit from, uh, the combination of kappaviertib and fulvestri, regardless of whether or not they, um, had a, uh, PPIC3CA mutation pathway alteration or not, whether they had a co-mutation in ESR1. Um, whether the, um, um, tissue, uh, tissue versus CT DNA tested positive. And so, I think, you know, you know, I think that it's, it's getting a little bit difficult to figure out which patients are going to benefit from some of these subsequent therapies when maybe all comers are going to benefit. I think we're, we still have more data to see and maybe some overall survival data would be helpful here. The last study I'm going to discuss today is the ascent study trial, the ascent 07 trial. This was looking at second-line ADC, um, this is saccetuzumab versus chemotherapy as first-line therapy after endocrine therapy in the hormone positive HER2 negative or HER2 low population. Um, And so, these patients had no prior chemotherapy in the advanced or metastatic setting. They did have measurable disease. They had one of the following, either two lines of prior endocrine therapy, uh, or progression after less than 6 months of their first-line endocrine therapy with the CD46K inhibitor, or primary resistance with recurrence with less than 24 months in the adjuvant setting. And they were exposed to a CD46K inhibitor in the adjuvant setting. This is a 2 to 1 randomization, um, of getting saccetuzumab, 10 mg per kilogram on days one and eight of a 28 day cycle versus physician's choice of chemotherapy, capecitabine, Paclitaxel, or, uh, NA paclitaxel. And the primary endpoint was looking at, uh, PFS. In looking at the demographics from this trial, most um. Um, I think what was most interesting was that 58% of patients in the cescetuzumab arm versus 57% of patients in the physician's Choice arm were considered HER2 low. 31% of patients had primary endocrine resistance versus 26% in the chemotherapy arm. Um, 89% of patients, 88% of patients had visceral disease. Um, and this did include patients with brain metastasis and bone only disease. Um, the PFS did not appear to be different by Bicker, um, in either arm. Um, they were not statistically significant. What was interesting is that in the investigator analysis assessment, we thought that there was some change in the median PFS 6.4 months in the physician's Choice chemotherapy arm versus 8.4 in the sascetuzumab arm with a hazard ratio of 0.78. The overall survival analysis is still, uh, immature, but trending towards improved, um, overall survival in the sasatituzumab arm. I think what's maybe most interesting here is what happened after this trial, because in the chemotherapy group, 61% of patients went on to get an ADC. And only 32% of patients went on to get an ADC after this. So, it's, it's almost a crossover trial without being a crossover trial. And so, I think, you know, this might answer the question of, you know, does it matter the sequence of ADC versus chemotherapy? Does it matter if you get it first or second? Maybe we're going to still be able to answer that question when we see the overall survival analysis come through. Um, and of note, sascetuzumab is an FDA approved option for patients after endocrine therapy and one line of chemotherapy. So I tried the best I could to try to summarize. What people in this room have done in the past 10 years, this is a busy slide, but I think we made a difference. You know, I think back to palbociclib first getting, you know, approved 11 years ago, and, and then came the other CD46K inhibitors, and then came P PARP inhibitors, and then came, um, Trastuzumabdexican, and then came the oral surges, and then came Dao DXD and then came involliib. I, uh, you know, we're, we're getting there. If you asked me to kind of figure out what are we doing for this patient, a CD46K inhibitor with endocrine therapy is still frontline therapy. 11 years later, that's still our best option. I, I think the bigger question is. Is what's next or how, how can we improve that? You know, I think, you know, when I think about what my clinic flow is about to look like and changes, I think I'm about to put a lot more pressure on my nurse, because somehow I need to order more. CTDNA testing on a regular basis. And I actually think in this room, that's going to be the bigger challenge. How do we get that done on a regular basis? How do we help prevent a patient from getting a 2 or 3rd needle stick when we all already saw them in clinic and say, hey, you have to go back to the lab and get another needle stick because you don't have a port yet, because we've been doing all of oral therapy. So, I, I think, I think there's a little bit more pressure on our nurses, um, and our APPs to help us figure out like, how can we make this easier on the patient, and that makes it easier on us to help make these decisions moving forward. I'm excited to see some new FDA approvals moving forward. Thank you.
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