So we're going to talk about, um, mostly hormone positive, HER2 positive breast cancer and a few abstracts that were covered at San Antonio. Um, we're gonna go back and forth and then hope to have a little bit of discussion in between, um, uh, about how we would apply this to our patient population. So again, 6 year old, uh, female with T2N1, uh, triple positive breast cancer. Uh, these are our disclosures. I have one and heliism. OK, so the first, um, abstract that we wanted to cover was the Margo trial. This was presented at San Antonio by Doctor Watts. And so this was a randomized phase two trial comparing neoadjuvant Paclitaxel, margitutuximab, and Pertuzumab versus Paclitaxel, trastuzumab and Pertuzumab in patients with stage 2 to 3 HER2 positive breast cancer. And so just to give you a little bit of background and rationale for this trial, um, obviously a lot of us know that trastuzumab acts in part via immunologic, uh, mechanisms including. Antibody dependent cell-mediated cytotoxicity and margitutuximab is an anti-HER2 antibody as well with a modified FC portion, uh, engineered to increase, uh, antibody dependent cell mediated cytotoxicity. So in the Sophia trial, Margitutuximab plus chemotherapy modestly improved, um, outcomes over trastuzumab and chemotherapy in patients with HER2 positive metastatic breast cancer, and there are known polymorphisms in the CD16A that affects the binding of margitutuximab and trastuzumab. And so the benefit of Martuximabb was more pronounced in the Sofia trial in the CD 16AF allele carriers. And so the hypothesis for this Margo trial, um, was that Margtuximab would be even more effective in early stage HER2 positive breast cancer, specifically with the CD16F allele. And so the schema is here up on the screen, uh, like we mentioned, it was stage 2 to 3 HER2 positive breast cancer. They could have any hormone receptor, uh, status. They had to be treatment naive, and they had to have a CD 16A genotype of FF or FV. They were randomizing a. One ratio to neoadjuvant TMP, which include marchituximab or neoadjuvant THP, which include trastuzumab, and that was for 12 weeks. So I wanna make note that they got 12 weeks of chemotherapy, um, which is not our typical standard, uh, length. The primary objective of this trial was to compare rate of pathological complete response in patients with HER2 positive early stage breast cancer, um, treated with TMP versus THP. So just a couple of notes about the patient population that were included on this trial. The majority, about 80%, were T2, um, around 65% were node negative, and around 65% were hormone positive. So these are the main results, um, so the primary endpoint for this study was pathological complete response, um, and so there was an absolute difference of about 10% between the two arms, but this difference was not statistically significant, um, with the P value is 0.25. Uh, secondary endpoint was PCR rates, uh, broken down by hormone receptor status and so there was no statistically significant difference in the rates, um, for either hormone positive or HER2, although the authors did mention that in the hormone positive, um, subset there was a trend towards a. Higher PCR rate in those that received margitutuximab with TMP versus those that received, um, trastuzumab with THP. And then in the hormone negative, the opposite was seen where there numerically was a slightly higher PC PCR rate in the THP arm, but again, neither of these were statistically significant. They also looked at, um, another secondary endpoint that they had was PCR rates by the CD 16A genotype, um, FF versus FV. And they found that the difference in PCR rates between the two arms was the same regardless of whether you had a genotype of FF or FV. Um, as far as adverse reactions, uh, both were actually very well tolerated. Um, over 90% of patients on both arms received all four cycles of the chemotherapy. Um, one grade 2 + AE was actually higher in the TMP arm by over 10%, which was infusion related reactions, but the authors did note that all of these reactions were manageable and all the patients were able to be re-challenged without issue. So in conclusion, uh, there is no statistically significant improvement, uh, in PCR rate with TMP compared to THP and regardless of the CD 16A FF or FE genotype. They did note that given that numerical improvement in TMP, uh, with patients who, um, uh, the TMP arm and patients with, um, In all PCR rates, sorry, with TMP, they do want to further investigate this and so they are looking at comparisons of circulating and tissue immune biomarkers across those two arms. Again, like we mentioned, safety and tolerability where this were similar aside from fusion-related reactions and all patients, um, are continued to be followed for event free survival. So Hayley, um, obviously, you know, we don't, we really have our only approval for Martuximab in the metastatic setting, um, and so I'm curious given that this is, you know, being utilized in this trial and the neoadjuvant setting, you know, do you feel like this will ever kind of play a role in your clinical practice or could you see this as a role in your clinical practice in any way? Well, I, you know, boiling this study down, we're looking at the same chemotherapy and the Pertuzumab is the same and really just one arm looking at the Herceptin or trastuzumab with the other arm looking at margituximab. Um, given that the path CR rates were not statistically significant, significantly different, um, I really don't see that this is a practice changing study and I don't think that there's enough of a. You know, a difference in the, um, kind of set up here that would change general practice, um. You know, of course, if the outcomes were a little better and we could swap 1, um, HER2 antibody for another, I think that'd be something that we'd really put some thought into. But, um, you know, although margituximab is a really nice option for pre-treated patients in the metastatic setting along with, you know, uh, chemotherapy backbone, I don't really see this as a, as a study that I would be implementing in my practice. Yeah, that's a great answer. Yeah, I agree. I completely agree. Mhm All right. So, um, continuing on with our, um, early HER2 positive, uh, breast cancer, looking at the touch trial, um, which is, uh, palbociclib and letrozole versus weekly Paclitaxel, both in combination with the anti-HER2 backbone, restuzumab with, um, pertuzumab in the neoadjuvant setting, um, so called the touch trial. So a little bit of background here, um, authors pointed out that early, early stage, um, HER2 positive and ER positive breast cancer is an unmet need, given that these patients have lower pathologic complete response rates than do the ER negative, um, HER2 positive patients. And there's been a lot of looking in now curative intent and also metastatic setting about adding CDK46 inhibitors onto a, uh, HER2 antibody backbone. And, you know, thinking about how we might target patients for this to be an effective de-escalation strategy in patients that, um, we perhaps would not want to expose to chemotherapy. However, um, biomarkers are lacking as they are in many of our, um, tumor types. Um, so the authors were particularly interested in looking at this, um, gene expression profile called RBSIG that, um, is an 87 gene profile that, um, That looks at functional loss of RB1. So they assign patients to RB SIG high, um, which would, which would predict resistance to CDK 46 inhibitors and sensitivity to chemotherapy and RBIG low with the opposite where you'd predict that these patients would, um, respond to CDK 46 inhibitors. So hypothesizing that this RB SIG gene expression panel may help us identify patients where we could better de-escalate, uh, neoadjuvant therapy to include a, um, non-chemotherapy backbone. So this was a study, um, run in Europe across multiple sites, um, looking at women who were post-menopausal. Um, of note, initially, this was a study just for patients 65 and older, and they did attend it, um, I believe due to slow accrual to allow all patients who are post-menopausal, um, These patients were, um, had at least T1C disease with N0N1 and, um, hormone receptor positive HER2 positive disease confirmed centrally. There were 145 patients that were randomized 1 to 1 to receive either Paclitaxel plus HP. Um, for, um, 4 cycles of chemotherapy, chemotherapy plus an extra of HP versus a non-chemotherapy arm, palbociclib, letrozole for 4 cycles along with, um, Herceptin and, um, Pertuzumab. And then patients would go to surgery. Um, baseline characteristics were well matched between the two arms. Again, small study, median age, they, you know, were looking specifically at a, an, um, a more, um, advanced age population. And just to point out that the majority of these patients were node negative. Um, the authors of this study pointed out, or pointed that the, um, the, not, not surprisingly, the non-chemotherapy, um, group had, um, higher rates of completing the full 4 cycles of treatment, uh, 94% versus about 80%. And there were also not surprisingly, much fewer, um, patients who had to discontinue, uh, treatment, um, due to side effects. Uh, 16% in the chemotherapy group, about 3% in the, um, pelvicilib arm. And overall, very high rates of completing the, the, um, 5 cycles preoperatively. Um, pathologic complete response rates, interestingly, between this chemotherapy plus HP, um, versus CDK plus letrozole plus HP were actually nearly identical, um, about 33% in, in both groups. Um, again, very small numbers here, but, um, but equivalent rates, um. And their gene expression profile, this thing called RBSIG, there was no significant interaction. So there, this was not a good predictor. And again, that tool was trying to predict which patients might have a better response to Paloiclib versus chemotherapy, and that did not pan out, um, with no differences between the RBI high and RBC low. So the conclusions of this study, um, were that ultimately, again, small study, um, in an older population of women with hormone receptor positive, HER2 positive breast cancer, looking at a de-escalation strategy with aromatase inhibitor, CDK46 inhibitor along with HP. The authors pointed out this was quite well, you know, very well tolerated, um, and had a pretty good activity. So thinking that this could be a nice alternative for patients where we're trying to think outside of the box who may not be, um, you know, someone who's eligible for multi-agent chemotherapy in the neoadjuvant setting. And, you know, on our ongoing quest to find biomarkers to predict which patients are matched to which treatments, you know, this one was not, um, a huge success with this 87 gene profile that they chose. And the authors concluded that the decent response rate and the good tolerability certainly favors ongoing study. I think that's the last slide with this. So, um, for the touch trial, you know, Melissa, I certainly see this possibly being able to fit into our current day practice. What do you think? Who, what patient might you think about this for? And would you feel comfortable giving a non-chemotherapy, uh, you know, approach to, to a patient of yours with HER2 positive hormone receptor positive breast cancer today? Yeah, I think that obviously this is very different than what we do currently in regards to the, you know, standard of care being chemotherapy plus HP, um, but we all have those patients that either don't want chemotherapy, um, are very against chemotherapy, um, which this would be a very, you know, with a 30% PCR rate with no chemotherapy, that's pretty impressive and so I think that this would be a good option for people who are adamantly against chemotherapy but still can get the benefit of some combination therapy. And then also we have older patients, more comorbidities who I have used like compass like trial with THP for, you know, um 12 weeks and you think dose reduced Taxol, I can make this happen and I have had instances where that still is extremely hard to get through for certain patients and if you look at the toxicity profile between these two, even with, you know, um, the chemotherapy. Versus this, this is much better tolerated overall and had in exactly the same path CR rate and so those patients that maybe before I was doing a dose, you know, dose reduced THP I would more consider this now given that it's better tolerated, lower risk of like de-escalation and lowering of the dose, um, which they saw on the trial as well and so I think I would start to incorporate this definitely into practice in those patients. Yeah, I agree, um, you know, I think that it's, it's not that common that we would see someone that we're so worried that we wouldn't want to give them any chemotherapy, but we do have these patients certainly they're, they're out there and, um, you know, sometimes you worry patients might crumble, you know, with the chemotherapy and being able to offer, you know, 5 cycles with a of a non-chemotherapy, um, you know, option. Very well tolerated, um, you know, and we have this data now 30% path CR rate, pretty good. Um, so I, I agree with you. I do see this fitting into our, um, into our practice. Awesome. Oh sorry OK, so the next, um, abstract that I'm gonna present is, um, a follow up data from the DTP, uh, trial, and so this was presented at San Antonio by Doctor Nara, um, and this presentation was a follow up of their previously presented, as I just mentioned, DTP trial. So this was a multi-factor analysis for pathological complete response in a chemotherapy free regimen of Divalumab, trastuzumab, and pertuzumab in HER2 enriched early breast cancer. So, um, this, uh, was it like I mentioned, chemotherapy, uh, free neoadjuvant, uh, trial, and so, um, in this trial they attempted to identify patients who are exquisitely sensitive to anti-HER2 therapy, um, that would maybe only have to be treated with DTP, so a chemotherapy free regimen. All patients had to be stage 1 to stage 3. they had to be hormone negative, HER2 positive, um, primary tumor over 1 centimeter, and they could have any nodal status, and there were only 39 patients, uh, enrolled in this trial and so, um, all patients receive 6 cycles of. Trastuzumab and Pertuzumab, and then they were stratified based on as to whether they were responders or non-responders. And so those that were responders all went on to surgery and those that were non-responders then underwent physicians' choice of salvage neoadjuvant therapy, which was universally TCHP. After they completed their salvaged new adjuvant therapy, they also went on to surgery and then they are again stratified. Um, after surgery, they had a complete, uh, after they, um, went to surgery, if they had an RCB or residual cancer burden of 0 or 1, they completed one full year of DTP um and everyone else who did not have an RCB 0 or 1 completed 1 year of standard adjuvant HER2 therapy for the Catherine trial. So the primary endpoints I, um, put at the bottom there. So primary endpoint was the rate of pathological response rate, and this was measured by residual cancer burden of 0 or 1. And then secondary end end points included PRR rates on PDL1 being over 1% or less than 1% and till status. There's also 3 year disease-free survival and safety data. So this was the um the pathological response uh um data that was previously presented at AACR um but just to show you and remind you roughly 2/3 of the patients, um, were able to achieve a pathological response and almost one half of those were actually able to achieve a pathological complete response. Now they also, um, went on to, it's not showing as well. There, but, um, they also went on to include patients who were initially non-responders who then received TCHP salvage, and they found that the pathological response rate, um, went up to 75.7% and the pathological complete response went up to 56.8%. So they wanted, the presentation was mainly based off of the next few slides. So they wanted to really dive into the data a little further and see if they could better understand, um, or better predict who may respond to this, um, targeted therapy and chemotherapy free. So, um, they want, as we can see, um, you're looking here at PCR rates and so you'll find that the highest PCR rates were in smaller tumor size, so T1, stage one tumors. Um, they also saw it in patients with tills over 10% and patients with CPS scores over 10%, um, and that all four of these were more likely to have a pathological complete response. They also, um, utilize the HER2 um DX signatures um to to assess whether that affected uh patients rate of PCR and they did find, um, some statistically significant associations so luminal differentiation signature, um, the proliferation signature, and the model PCR scar all correlated with patients having a higher rate of PCR, um, in receiving the DTP. So they also went on to look at single cell, um, single cell sequencing, and they wanted to analyze it to see if they could use single cell sequencing, utilizing both their, they had tissue from the primary biopsy tumor and then after surgery as well, and they were able to pair the two. And so the overall data, um, which is a little bit of a busy slide, but I'll walk you through it. Um, tells us that responders at baseline as compared to non-responders at baseline had more, um, different cell makeups, and what they found is that, um, those that were, um, responders at baseline had higher percentages of both plasma cells and B cells, which would make sense and then patients who were non-responders had a higher percentage of myeloid cells both at baseline and at end of treatment. So it seems that those patients that are seem to have more immune potential respond better to the, to the DTP and with the resulting PCR. And so they went a little bit further in looking exactly at those myeloid cells. And so they wanted to understand what they were indicating. And so they looked at the subset of myeloid cells and you'll see. That the nonresponders had significantly higher rates of SSP1 positive tumor associated macrophages as compared to those that were uh responders and we know from previous publications that SPP one tumor associated macrophages are associated with chemo resistance and worse clinical outcomes so it makes sense that the non-responders would have obviously a higher proportion of these cells. And so in conclusion, um, in this HER2 enriched breast cancer, um, de-escalated Darvelumab, trastuzumab and Pertuzumab was well tolerated and it did achieve a high response rate with a PCR of 49% and a PRR of 68%. Um, several clinical and pathological parameters correlated with pathological complete response as we mentioned, so smaller tumor size, um, earlier cancer stage, higher tills percentage, and PDL1 CPS scores. And then also we found in a mole they found in a molecular analysis um that there were several factors that correlated with PCR that we went through including a large proportion of B and B cells and plasma cells and a lower proportion of SPP1 positive TAMS. Um, they did not, uh, uh, present the extensive safe safety data, um, during this, uh, presentation, but I'm curious, Hailey, um, you know, I think this is really. Interesting. It's a chemo chemotherapy free, um, uh, option for patients and so I'm curious if you feel like this is something that you know is ready to further explore or are we need do we need to be able to be making more identifiers of who would achieve that past CR before we upfront give them 6 cycles of something and then have to give them another 6 cycles of a salvage chemotherapy, um, afterwards. OK, our last one. Um, so, um, still thinking about early breast cancer, but now looking at, um, HER2 negative hormone receptor positive breast cancer. I'll, um, move quickly through this. Um, so this is a case called Salty Valentine, um, that came out of Spain. This study is looking at a, um, an antibody drug conjugate that's, uh, HR, HR 3DXD, um, alone or in combination with letrozole for patients with, um, uh, curative early breast cancer, that's hormone receptor positive and HER2 negative. Um, a little bit of background, of course, multi-agent chemotherapy remains backbone for these high risk hormone receptor positive patients. But of course, we're, um, you know, giving a lot of toxicity and, and perhaps marginal efficacy in some of these patients. And, um, as everyone is well aware, we have these great ADCs that are showing a lot of promise in the metastatic and adjuvant setting. So can we start to bring some of these up to the neoadjuvant setting? Um, HR 3DXD is a, um, ADC targeting this, um, HER3, um, uh, surface protein, and it has shown in, in prior studies, um, pretty good activity in multiple subtypes. Um, ultimately, this study, again, small study, um, uh, 120 patients randomized 2 to 2 to 1 to receive this ADC versus ADC plus letrozole. Remember, these are hormone receptor positive patients versus standard chemotherapy, which was essentially a dose stents ACT type of backbone. Um, and then patients went on to surgery, primary endpoint looking at rates of pathologic complete response. Um, ultimately, these were actually, um, fairly fairly advanced patients with, um, a majority or a decent number of patients, um, with T3 and T4 tumors, um, and majority lymph node positive as well. And I just wanted to point out this HER 3, surface marker. The majority of patients were considered HER 3 high. Um, so this was not like a, a, a, a marker that you have to select for thinking of, um, Trestuzumabects to can with the, um, IHC that initially showed the best benefits in the, in the high expressor. Um, so, ultimately, um, path CR rates and, um, overall response rates were, were quite similar with the, um, antibody drug conjugate as compared to the chemotherapy. But as you see here, quite small numbers, um, very small rates of pathologic complete response, um, perhaps not so surprising given the tumor type of hormone receptor positive, HER2 negative, um. This was a, um, a well-tolerated drug. Um, ultimately, there was no, no cases of ILD, um, and they pointed out that toxicity was, was a lot better than the multi-agent chemotherapy. So conclusions here, um, we saw similar, albeit low, uh, rates of pathologic complete response and high overall response rates similar to those seen with chemotherapy. Um, we see, I didn't go through this for purposes of time, but again, looking for this marker. Um, the, the study did show that, um, with the cycle 2 biopsies, um, that these tumors were being converted to less aggressive, uh, phenotypes, which would indicate that there is good anti-tumor activity with this ADC. Um, these patients tolerated treatment pretty well, and the authors concluded that they certainly recommend including, um, this HER 3DXD ADC in, uh, future studies. So are you ready, Melissa, for, um, HR 3DXD to join our milieu of drugs? You know, should we welcome it with open arms here? What do you think? Well, I think it's impressive that it has the same, um, overall response rate I think you said like 70%. I mean the PCR rate was quite low, which, you know, this patient population. I know there was a question during the discussion after this at San Antonio being like if this is a high genomic risk population, how was the PCR rate so low? And it turns out that most of the patients on this trial just had a key, uh, 667 over 20% and only one actually had a procigna that was elevated. So, um, even though that's an inclusion criteria, the majority of the patients didn't. Have a high, uh, genomic, um, assay like, uh, Proscia so you know maybe with a different patient population we would see a higher, you know, uh, PCR rate, but I, you know, it was really well tolerated it had lower AEs compared to, um, significantly lower AEs compared to chemotherapy. So I think it's another situation where we have. Options for patients who we don't think necessarily will tolerate chemotherapy. I don't think it's like, you know, prime time yet. Obviously we need more um data on it, but I do think it's a very, you know, we're moving a lot of ADCs into the neoadjuvant setting and a lot of them have, you know, ILD concerns and other toxicity concerns, but with the profile of this, I would be, you know, very interested to see if we could use it in a select patient population, um, who we want, um, at least to start and then maybe move it to more general population. Yeah, so I think that's it for case 11. All right, everyone, that was great.
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