Chapters Transcript Video Human Epidermal Growth Factor Receptor 2 (HER2) Disease Updates Hi, everybody. It is great to be back uh to be back in person and to see so many familiar faces and uh like Rich, I also have a very brief presentation. And so, all right. Um my topic is her two positive breast cancer. There are my disclosures. Um And so I have four abstracts to tell you about, but I wanted to kind of put them into context first and just thinking about where we are with her two positive breast cancer in 2024. So we know this treatment for her two positive breast cancer continues to evolve and that antibody drug conjugates have really now provided another level of benefit beyond the era of monoclonal antibodies. And with more and better treatments, we now have the obligation to start thinking about how can we optimize strategies. That means we want to maximize survival and minimize toxicity based on using the best drug for the best for that patient at that time. And we know that there are these interesting emerging data for patients at the extreme. So there are patients with an extremely good prognosis. And we want to think about how we can give them less treatment because some of them may actually even be cured in the metastatic setting. And there are patients with incredibly poor prognosis still refractory to our her two directed therapies. So there are different questions depending on the type of her two positive breast cancer, particularly with regard to how patients respond to therapy. We have emerging biomarkers to try to help us assess what group these patients are in like her two DX and target print. But these are not yet used routinely in clinical practice. And it's not 100% clear what the utility of those will be. And finally, the role of immunotherapy therapeutically is not clear. There's very little work that's been done yet to think about how we might integrate immunotherapy into treatment of her two positive disease and then her two positive er positive disease. I would argue is a really different entity from her two positive er negative disease. Um But we don't yet really understand the best way to treat it what its ultimate prognosis is and how it behaves differently, particularly over the time horizon compared to the er negative group. So in that context, let's talk about the abstracts. The first was her two climb two. And so this was a double blind phase three trial of two cat NIB and trans two zab M tin or TDM one who previously treated her two positive metastatic breast cancer, anxiously awaited results after her to climb one. So juat nib as many as you all hopefully now know is a small molecule TK I it's highly selective and it penetrates the blood brain barrier. And that is one of the most important compa um uh features of this drug. So the her two climb trials are really examining the benefit of two cat nib to approved her two directed therapies. We had her two climb one that looked at and found a progression free survival and overall survival benefit to adding to cat Nib to keep sight of be and Tres two. And now we have her two climb two, which is switching out the chemo trastuzumab partners to use an antibody drug conjugate TDM one. And you can see in the green box, the um pretty standard eligibility. But I point out to you that this trial included patients who had previously treated stable or progressing or untreated brain meds not requiring immediate local therapy. So clearly here we want to start to look at whether toat NB can improve outcomes for women who have brain meds. You see it was a trial of 460 patients with a randomization 1 to 1 to TDM one and two catnip versus TDM one and placebo with very standard uh doses. And the primary end point was progression free survival by P uh investigator assessment. And that analysis was planned after 331 events with 90% power to uh uh detect a hazard ratio of 0.7. So here are the results in a nutshell, there was a significant progression free survival benefit in the overall population with a hazard ratio of 0.76 a highly statistically significant P value. And you see that, that Kaplan Meyer, which is on the right with about a two month benefit um in this population to the addition of two catnip, the progression free survival in all subgroups favored the TCA nib arm. And then below, you can see the progression free survival in the brain met patients. And here again, we see that there was a significant benefit to toat nib uh with hazard ratio of 0.64. And uh we see that again, that provided a benefit of about two months in progression free survival among patients who had brain metastases, the overall uh survival benefit uh was not seen, but that data really is not mature yet. Um But it's important to about 50% of the patients have gotten TDXD and 15% have gotten subsequent to catnip. So it may be a little bit hard to in uh interpret that overall survival data and there was really no additive or synergistic toxicity by combining these agents. So I suspect that we will be seeing this emerge as another treatment option for us in the near future. Moving on then to the question of immunotherapy given with her two positive disease, we have the aviator trial A T BC RC. Trial that was a randomized phase two, looked at Varel bean and tres two zab alone or in combination with either a vab or a volume and a really novel drug aye. I practiced that even uh in her two positive metastatic breast cancer. So again, we have not really delved into the full benefit of immunotherapy and her two positive disease. But we know that monoclonal antibodies work in part through immune mechanism. So it stands to reason that there could be some benefit to trying to further augment the immune response in these patients. And we know that these antibodies can work through uh A DC C and A generation of adaptive immunity through CD eight T cell activation. And that is important because the drug, the really novel drug here, the um omy uh is uh basically targeting 41 BB on activated T cells. And so we already knew that T cells were important here in uh the response to therapy, 41 BB on activated T cells and NK cells increases their cytotoxicity. And in preclinical models was synergistic with trastuzumab. So the goal here was to try to understand whether one could get an improvement uh in uh progression free survival with the addition of either just the avelumab uh immune checkpoint inhibitor or the uh addition of both the checkpoint inhibitor and the 41 BB inhibitor. So this was advanced disease. Patients had to have prior res Tuum Pertuzumab and TDM. One they could not have had any prior immunotherapy or uh venal bean and they were not selected on the basis of PD one. I'm sorry, PDL one. And you can see that is a 1 to 2 to 2 randomization to just the doublet standard of care. There are 20 patients in that arm. Uh and then 40 patients in the triplet and 40 patients in the quadruplet uh with co primary end points of comparing both of the investigational arms uh to the others. Um Interestingly and importantly, while this trial was going on in 2021 util mim A was stopped in terms of development. And so what the investigators did was say, well, we have these dual primary end point. So let's just take a look and do a a futility analysis of the patients who were on the quadruplet arm. And uh what they found was that there had been no benefits seen to adding the mi A almost got it um over the triplet. Uh And so there was no concern here that they were missing out on something if they were to drop that arm. So the trial proceeded with just the two arms. So here are the results comparing those two arms in green, you have the triplet red, you have the doublet or at the end of the day, 60 patients uh 20 on the doublet 40 on the triplet stratified by E status and whether or not patients had liver metastases. And even with just this abbreviated uh group of patients, they had 88% power to detect an increase in progression free survival from 2 to 4 months. What they found was an overall response rate that was higher with the triplet 11% versus 20%. And an improvement in progression free survival of 1.8 months. Pretty close to that detectable two months, moving from two months to 3.8 months. There was a similar result when they looked at this um based on the number of tills in the tumors, there was no additional benefit seen amongst the patients who had PDL one positive tumors. However, let's remember that this is a really small study. So any additional biomarker work is gonna be very underpowered, there were no unexpected safety signals. And on the basis of this result, there is interest in trying to take this triplet forward to see if this is truly a signal. So here I would say that there was, while there was a significant sig signal with the IC I alone, it was actually a modest benefit in this very highly pretreated cohort. So it's important to recognize that in this study, patients had up to 13 lines of therapy. We know that immunotherapy seems to work best the earlier you move it in the treatment trajectory. And so we might even see a greater benefit if they were to move it up further into first or second line, I still think we have a long way to go to fully exploit immunologic response. But I think that really given this um extraordinary response, we see to her two positive disease with cytotoxic treatment, perhaps another strategy would be to try to get patients to a minimum level of disease and maybe use an immune based maintenance in the metastatic setting to try to uh to, to exploit this vulnerability because again, it does seem to work better, the less disease you have and the earlier you use it. So then we move on to the issue of her two positive er positive disease. And here we saw the presentation of the aspire trial, a multi center phase 12 trial of Anastrozole palbociclib, trastuzumab and Pertuzumab really looking at whether you could give a chemo free regimen to patients who are her two positive and er positive. So even though we know that these patients have two things on the surface that we could be targeting the current standard of care still remains that cleopatra regimen where patients start with a taxing and add the two antibodies with a survival advantage. I think the question would be um the survival of advantage occurred in Cleopatra at a time. We really didn't have a lot of other great drugs for her two positive disease in the metastatic setting. And that landscape obviously has changed very much. And so we really now want to see if we can get away from using that toxic taxane right up front because we have a lot of patients who present with pretty low volume disease. We know they're going to respond well and yet we're giving them taxane and they lose their hair and have a lot of other side effects that really adversely affect their quality of life. So it is really worth trying to figure out if just by optimally targeting these two pathways, we could get away from having to give patients chemotherapy. It's a little bit small. It isn't really important the details here. But there was a phase one section where they escalated palbociclib to see what the optimal dose would that of that would be along with standard doses of the anastrozole, trastuzumab and pertuzumab. And then ultimately took that, that uh MTD Palbociclib forward in the quadruplet uh with a primary endpoint of clinical benefit rate. So the study population ranged in age from 31.6 to 82 with 73% post menopausal. 43% of the patients had de novo metastatic disease and 63% of the patients had visceral metastases. 30 patients ended up in the phase two portions and 30 months was the median follow up at the time of this analysis. And what you can see was that there was incredibly high clinic clinical benefit rate, 97% and a very high objective response rate. 73% with um that uh including that's just the patients who had both a complete and a partial response. I don't think this is necessarily a surprise to any of us, but I think we needed this data because there are many patients that we'd love to go this route. And we'd really like to have a good sense of whether A it's well tolerated. And B we're expecting to see a high risk rate, you can say see that it took about three months uh to uh reach a res a response and um that the median duration response was 37.8 months. So I think that we are moving away from needing to give chemotherapy to patients right up front and this data and others will really support that decision. I do want to just point out that they showed both the pfs and the overall survival data. And so what you can see a couple of notable things here is a big drop off in PFS at six months and a big drop off at 18 months. And the other thing, you should look at this and say, wow, look at how that drop off happens with PFS. And yet we see this incredible overall survival with, you know, most of the patients still alive at 48 months. And that really tells you that we have excellent therapies to give to these patients after this therapy so that it is a little bit hard and it's going to be increasingly hard to really understand whether the first line therapy is gonna long survival because we have so many other wonderful therapies for these patients regardless. I think that there are some things that came out of this are, are very valuable. We saw that there was a high response and clinical benefit rate and an almost two year medium pfs and that we had an overall survival that is extremely high at four years. And that is good news for our patients. I think we leave with some key questions. What's the role of additional agents that were given post progression? How long did these patients get to avoid chemotherapy overall in the trajectory of their disease? And then importantly, who are those patients who are progressing at six months and at 18 months? Because those patients might give us some keys to resistance and need other approach. And so if we could identify those people upfront, we could figure out who may be doing well with this approach and who might actually need chemotherapy right up front. But I do think this provides a really important foundation for finally eliminating the need for a taxing in every patient. Now, we're just gonna end with two studies that look at treatment in the elderly. So this is the herb tea studies. So I totally love the name of this trial. Um And it's from Japan, not surprising although it has nothing to do with herb tea. Um It is a phase three study that it compared TDM one with trastuzumab pertus mendosa Taxol. So the cleopatra regimen with TDM one upfront in older patients to get a sense of whether there was a benefit because older patients may be particularly susceptible to the debilitating side effects of taxanes. And so the question is, could we give a less toxic regimen? I think to some extent, I'm not 100% sure TDM one would really be considered a whole lot less toxic, but it is somewhat less toxic. And that was the question that they asked patients in this trial had to be over the age of 65 and have a prog um a performance status of 0 to 2. And you see those two arms um 75 and 73 patients respectively, they had a target enrollment of 250 patients, but they stopped early because an interim interim analysis of overall survival uh exceeded the non inferior margin. So what you see on the far right at the top is the Kaplan Meyer curve for overall survival with the TDM one arm in red and the THP arm in blue and clearly the THP arm was better. Um And in this patient population, which truly was on the older side with patients up to 88 years old, which had more than 50% positive patients. Um really good performance status. Almost 100% of the patients had a performance status of zero or 1 65% of them were stage four and 58% had an adjuvant resume, 65% have visceral metastases. You see the progression free survival also suggests that um patients with the THP did better than patients with TDM one. And then lastly, this observational study looking at chemotherapy versus non chemotherapy in patients who had early stage her two positive breast cancer from the National Cancer Database. And um again, there's very little data on tolerability and benefit of treatment as women age and decline in health. The current standard of care includes chemotherapy. So the question is, do we really need it even in older women who may have comorbidities that limit their survival? So the question here was, could we give less to older women to help them avoid the toxicity of chemotherapy? The National Cancer Database is a joint program of the Commission on cancer from the American College of Surgeons and the American Cancer Society has over 1500 cancer programs around the country that contribute data. So this is a really nicely representative um group of centers and what these investigators did was model the relationship between mortality and age to determine if there was an age cut off at which chemo added no additional benefit to monoclonal antibodies alone. And what we saw here in this data was that outcomes were significantly worse when they uh did not receive chemotherapy or if they for uh forewent treatment altogether. Compared to standard of care. Now, of course, it's incredibly important to recognize that this is full of selection bias, right, that the patients who get chemotherapy are in general going to be healthier because the doctor thinks that they can tolerate chemotherapy. And so their survival may have very little to do with the treatment itself. But more over the selection of which patients could tolerate treatment, regardless, there was no age at which this phenomenon did not occur. So across the board, it was always always better outcome if patients got chemotherapy and you can see there um Multivariate models uh that that were both very highly significant um either for dropping chemo and just giving the monoclonal antibodies or for giving no treatment at all. So I think in summary, what these data tell us is that treatment optimization continues to be our goal and we have a lot of new agents. Um and they're helping us figure out ways to give these therapies in more appropriate um strategies that can give us better outcomes with her two climb two TDM 12 kib may be a new combination of benefit, particularly for patients with brain meds. We aren't sure how this exactly is going to change the strategy and where we're going to fit it in. But it does have the potential to bring to catnip up earlier into the treatment sequence. Aviator showed us that some patients may benefit from the addition of immunotherapy. But we still need more data on how to optimally use immunotherapy. In this patient population aspire, showed us that we can continue to work on regimens that have less chemotherapy or use it later to avoid toxicity and do well in certain populations of patients, particularly this group that are her two positive er positive, positive. And so we still need more data on how to select those patients. And then finally, with older patients they need and they deserve the best treatment that they can tolerate. And age is simply a number. So we really need to look at their biological age, their overall um performance status comorbidities and give them the most. We think that they can, that they can tolerate. And we really need more information on how to factor in functional status and ch chronic health decisions, uh conditions and how we make decisions about care. And with that, I will end. Thank you very much. Created by Related Presenters Angela DeMichele, MD, MSCE
