Right, we have a 72 year old woman who presents to the office with metastatic invasive ductal cell carcinoma, and this is an ERPR positive, HER2 negative or HER2 low breast cancer. Uh, she has metastatic disease to the bone and to the liver, but she is asymptomatic, uh, with mild back pain. She has no prior therapy. OK. Everyone likes the endocrine and CD46K inhibitor. Disclosures and then um I'm gonna go pretty quickly through this one because um it doesn't, it's not as practice changing and then give us more time to talk about your case and so this was the results um they presented the results of the PADMA trial which was looking, it was a randomized phase 4 trial looking at first line endocrine therapy plus palbo versus standard mono chemotherapy and with high risk hormone positive HER2 negative metastatic breast cancer that had an indication for chemotherapy. And so at the they made it very clear that at the time that they wrote this trial and started this trial, um, there was a lack of perspective data comparing ET with standard of care chemotherapy in the setting, um, and that many patients still received first line chemotherapy as treatment for metastatic disease when PADMA was initiated, um, and so this was the first, um, perspective randomized trial looking at this. And so this is the design, um, patients had to have an indication for mono chemotherapy. um, they had to be treatment naive in the metastatic setting and they could not have asymptomatic bone only or oligometastatic disease. Um, they were randomized 1 to 1 to either endocrine therapy with elbow versus chemotherapy or physician's choice. Um, after chemotherapy or physician's choice, they could go on to receive endocrine therapy as a maintenance therapy. And the chemotherapy that was used or allowed to be used was Paclitaxel, cape cytabine, um, epiruin, and vinarebine. So the study endpoints, um, the primary endpoint was time to treatment failure. And then secondary endpoints included PFS, OS safety. They had several others, but they did not cover them in the talk at San Antonio. Um, just wanted to mention that, um, majority of the patients who discontinued, um, discontinued for progressive disease, 42 in the chemotherapy-based arm, and 32 in the endocrine-based arm. And so looking at baseline characteristics, 88% of patients were postmenopausal, uh, about 50%, 40, closer to 40% had liver metastasis, um, and, um, there was about 30% across the board that were endocrine resistant. And so of note, the majority of chemotherapy that was used was cap cytabine, uh, 70%, and then Paclitaxel at 30% and very few vinayl bean, and about 22% of all patients went on to receive endocrine maintenance therapy after chemotherapy. And then as expected for the type of endocrine therapy used, the majority was, uh, aromatase inhibitor and some, uh, 22% had full vetrin and none used tamoxifen other than in the, um, the endocrine, uh, maintenance arm. So the primary endpoints, um, did show a statistically significant improvement in time to treatment failure, um, favoring the endocrine therapy arm of 17.2 months versus in the chemotherapy arm which was 6.1 months, um, with a hazard ratio of 0.46 and a medium follow up of 36 months. And as you can see from the forest plot, um, most of them, um, strongly favored the, um, endocrine therapy as compared to the chemotherapy. Secondary endpoints, PFS is on the left and OS is on the right. So PFS was statistically significant. Um, 18.7 months was the median PFS for the endocrine therapy arm. And chemotherapy arm was 7.8 with the hazard ratio of 0.45. So both, um, time to treatment failure and, uh, improvement in progression free survival and, um, numerically there was an improvement, um, but not statistically in the median overall survival of 4646 months in the endocrine therapy arm and 36 months in the um chemotherapy arm. Uh, safety very well tolerated, um, mostly, um, hematological adverse events in the pavlocyclabb arm, um, compared to the chemotherapy arm, but again, 70% of the patients receive cap cytabine, so we would expect that, um, they would have, um, a lower rate of hematological toxicity as compared to palloiclib, but otherwise the other non-hematological toxicities were, um, comparable across the arms. So in conclusion, I mean it met its primary endpoint, um, it showed a statistically significant and clinically meaningful improvement in, uh, time to treatment failure and PFS for palvicycllib and endocrine therapy, um, and there are no new safety signals observed and so you know they made. Point in the discussion in the discussion of this trial also that no patients were in visceral crisis, um, while they had visceral disease, they were not in visceral crisis and so I think, I think we all feel very comfortable in not, um, treating patients with visceral disease as visceral crisis and utilizing chemotherapy in the first line, um, setting and the right choice trial and etc. other trials that have shown us the benefit of upfront CDK46 inhibitor, um, with endocrine therapy. Anything to add, Angela? No, what did you think about the, um, choice of chemotherapy? I thought it was pretty typical of what we do in practice, but I, I, I didn't think that there were there was anything unexpected there. Yeah, I think that, you know, for hormone positive, most patients were putting on keepsy of being in that situation, um, again, if this was visceral crisis that would be different, obviously, um, and it was interesting that this is mono chemotherapy that was compared to as, as the right choice child was against doublet chemotherapy, um, but still, uh, it reflects what most patients not most patients. Most of, uh, oncologists use in practice. I, I think that we're mostly saving chemotherapy for frontline for those with visceral crisis at this point. Exactly. I think, um, there's some bold, bold oncologists that will use the CDK 46 with like true visceral crisis and we have seen responses, but I don't think we have the data, um, given that other trials did not even include like a, uh, abnormal bilirubin, um, to in those patients who had visceral crisis. So, um. Definitely would save it for them. I think patients prefer the oral therapy over infusional 100% yeah. OK The, um, next abstract and last abstract that we're gonna be talking about is, uh, from the ER 3 trials. So this was looking at lunestrin, it's a new oral ser, um, as monotherapy and combined with Bemacycllib in patients with ear positive HER2 negative advanced breast cancer and also in patients with pre-treated, uh, with endocrine therapy. This was a phase 3 result, uh, phase 3 trial. Um, and so in thinking about, um, you know, the backbone of therapy for metastatic ER positive breast cancer, we're now using endocrine therapy and CD46K inhibitors, um, in this patient population. Um, and the continued suppression of the estrogen receptor and the CDK46, um, beyond progression on that therapy may be important for improved patient outcomes regardless of whether or not they have a PIC3CA or an ESR1 mutation. And we know that we're also using a bemacycllib in patients that are CD46K, uh, naive or in pre-treated patients. Um, as a single agent, um, Fulvestrin is the only sir that is broadly approved in monotherapy and in combination, but we know that its efficacy is limited in those patients with an ESR one mutation. It also requires that intramuscular administration that while patients make it through it, you know, it is, it is, uh, burdensome to the patient with a monthly appointment when oral options are available. Ellis strand is an oral surge with a dose dependent mixed estrogen receptornist and antagonist activity approved as monotherapy for those patients with an ESR one mutation. And again, Ilunestri is a next generation brain penetrant, uh, oral ser and a pure estrogen receptor antagonist that delivers continued ER, uh, estrogen receptor inhibition. Um, And just next to that are results from the phase one trial, um, that showed a great response rate when Ilou Nesttrin was combined with the Bemaylib. And so in the MBER 3 trial, again, this was a trial for patients with an ER positive, HER2 negative, advanced breast cancer, both, um, men. Um, and pre and post-menopausal women were eligible for, uh, enrollment on to trial. Um, prior therapy could include those patients, uh, that had recurrence after the adjuvant setting within 12 months of completion of an AI and a CD46K inhibitor or in the advanced breast cancer setting for those patients with progression. Um, on frontline, um, aromatase inhibitor and a CD46K inhibitor, and they could not have had any other therapy, uh, for advanced breast cancer. Um, they stratified based on previous, uh, therapy with the CD46K inhibitor, whether or not patients had visceral metastasis, um, and, uh, region is, uh, location, uh, in the, um, that they lived in, um. And so the primary endpoints, and this gets a little bit confusing, um, looking at, uh, Ilustrin versus standard of care, which could be fulvestrin or examsanne. Um, versus Mlulutrin with Abemacycllib by itself. Um, and the primary endpoints looked at, um, RMA and R&B in patients with an ESR mutation or in all patients, and then looked at Mlunestrin plus or minus, um, Abemacyclli in all patients, but did not look at those patients did not compare those two arms, um, if they had an ESR1 mutation. Um, secondary end points that were looked at were overall survival, PFS, um, and overall response rate, as well as safety, and there were several exploratory endpoints. Um, and looking at the basic demographics of these patients, um, I'll just specifically point out, um. The age of these patients was about 61 years old. Majority were female, majority were postmenopausal, um, majority were white with the surprising, uh, 30% of patients that were Asian, few black African American patients. Um, uh, this did, oh sorry, uh, this, uh, trial was open in East Asia, so that, uh, explains the Asian population. Um, this did include, uh, when they looked at the ESR1 mutation, about, um, 32 to 42% of patients had an ESR-1 mutation and about 40% of patients had a PIC 3K pathway mutation. Um, over 50% of patients had visceral disease with about 30% of those being in the liver. This did include patients with bone only disease. Um, Uh, this included 30 patients, about 30% of patients were being treated after progression in the adjuvant setting within 12 months. Um, And about, uh, 60% of patients had had a previous CD 64K inhibitor. Um, and looking at the primary endpoint, again, this slide is looking at lunestrin and Abemacycllib versus mlulestrint did show, um, an improvement in progression for survival, 9.4 months compared to 5.5 months, um, with a 43% reduction in the risk of uh progression or death in, um, In the mlulutrin and abemacycllib compared to mulletrin by itself. In looking at Mlunestri versus standard of care, um, the differences were not as significant, 5.6 months versus 5.5 months. And so this did not reach, um, significance. In looking at Ilunetrin versus, uh, the standard of care arm for those patients with an ESR mutation, you do see a little bit of separation in the curve with the PFS of 5.5 months versus 3.8 months, and this was thought to be statistically significant. In a subgroup analysis of comparing mlunestrin andabbemacycllib versus mlunestrin, um, they did see the, um, patients that had had a prior CD46K inhibitor, um, That the, um, addition of the Bemacycllib did seem to improve the progression free survival at 9.1 months versus 3.7 months. And for those patients with the PIC 3K pathway mutation, there is also still a benefit with the addition of abemacycllib. In looking at the subgroup analysis, it did seem in general to favor the addition of a Bemacycllib to lunestrine in most, in most arms, um, especially in looking at those patients with visceral metastasis and looking at patients that it had a prior CD46K inhibitor, maybe surprisingly did better when a Bemacycllib was added. Um, but no difference in those patients that had an ESR mutation, um, or PIC 3 CA mutation. And then looking at the subgroup analysis, only in those patients with an ESR one mutation, again, seem to favor Ilunetrin versus standard of care. In a post hoc exploratory analysis and comparing Ilunestrin to standard of care, the cumulative incidence of CNS progression did seem to favor, um, being on Ilunestri versus standard of care. The interim overall survival analysis in comparing mlunestrin to standard of care. Again, standard of care was fulvestrin or exameshane did favor immunnestrin. In patients without an ESR1 mutation, um, the maturity is only at 18%. Of this data. In general, the combination of mlunes, um, and amicycllib showed increased diarrhea when compared to imlunesran by itself, which is not surprising, but otherwise grade 3 events were only at about 17% for imlunestrin, 21% for, uh, standard of care. To a good safety, uh, tolerability. And so I, I think, you know, when I think about Ilunestrind, new oral ser, um, You know, are we, are we ready for, for endocrine therapy in the metastatic setting to gain a new drug? Um, yeah, I think obviously there's a lot of surges that are, um, coming out and will continue to come out with the ongoing trials. I think the biggest question is obviously this is in the ESR1 mutated population that will be utilizing this, and I feel like over the last year I felt more and more comfortable with sequential CDK46 inhibitors in selected patients based on the data that we have for that so far. So it, it makes sense to me to combine it with an oral ser, um, if I'm going to be doing that in the second line and if they have an ESR1 mutated, um, I think there's, you know, questions of should we be combining it up front, should we be doing it sequentially, um, but you know, full vestri, while it's annoying to come in every month and get an injection, um, is also very well tolerated, and the oral surs can have a lot of GI, you know, symptoms with them, but they are easier to take. They are more. Convenient for the patients and so I think it's up for debate, but I would feel because I'm utilizing more CDK46 ins you know sequentially, um, after other CDK46, it makes sense to me to do the combination in the ESR1 mutated if I would have been reaching for full vesture in that patient anyways in combination. It's also note that the standard of care arm is something that we don't do. Um, I don't think many people give single agent fulvestrin or AI in the second line therapy, um, so you know, when you compare those that data, you take that with a grain of salt, but you know, I think, I think you have a slide that was a really good summary. Is it going? It's coming. Oh, why isn't it? Oh, it's not there. Um, but it was the year in review at the end of San Antonio, um, and I thought it was a really nice kind of like flow sheet and, and how we would consider and look at these, yeah, agents, um, and so yeah, so I'm curious if you think, you know, would you go for the combination over, uh, Ellis Estrin in patients with a. Um, an ESR1 mutation who progressed on a CDK46 inhibitor. I, I, I think, um, you know, I think in, in the perfect world you would have, you would have had also an arm that was in lunestrin followed by Abemacycllib, you know, the question of do you need to use combination therapy? Can you use. Things sequentially spread out all the therapies that we have, you know, before we need to turn to IV chemotherapy is also just that other question that I always ask myself, um, and so I, I, I think that second line therapy is definitely biomarker driven as you know, as suggested by the slide, I, I think that we still need to get our feet wet. We have a lot of options which is a good thing, um, but makes it a little bit complicated and hopefully we'll have further studies to kind of help us with with sequencing but I agree I think um the data is con you know is it's good to have more options and more combination and also to see the safety data from the combinations as well. I think that's it. I appreciate all of you for sticking it out to the end. So a round of applause for all of you. All right. The winner of our poster first poster presentation was Doctor Lyons. Doctor Lyons, please come up to the stage. There we go. For all of you that have been waiting, you put your tokens in, you wanted to know, will I win that special prize? All right, you want to pick one out? Oh, you're gonna do we're gonna do it that way. It's like
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