ESMO 2023 Breast Cancer Highlights – Keynote 756, TROPION-Breast01, Keynote 52 | Onc Brothers

Welcome to ESMO 2023 Breast Cancer Highlights Hello everyone I am Rahul Ghasain and. I'm Rohit Ghasain and we are oncology brothers. A lot of data was presented at ESMO 2023 to focus on some key studies in breast cancer. From this meeting today, we're joined by a renowned educator and a clinician, Dr. Erica Hamilton from the Sarah Cannon Research Institute with Doctor Hamilton. We hope to discuss keynote 756IN High Risk early stage hormone Receptor positive disease. You can also look into Tropion breast O1, a new ADC in metastatic space and then close off with the update on KEYNOTE 522, our current standard of care for early triple negative breast cancer. Erica, thank you for joining us. Speaker 3 Absolutely happy to be here. Keynote 756: Immunotherapy in ER+ Breast Cancer America, to get started, we have Keynote 756 not only in triple negative breast cancer, but we are seeing more and more incorporating this approach of perioperative chemo immunotherapy. And now when we look at lung cancer, it's very similar in this large phase three study T1C to T2 with no positive or T3 to T4 rather high risk, basically an ER positive. Her two negative treatment naive patients were randomized to neoadjuvant pembrolizumab with chemo versus chemo alone and placebo. And then pembrolizumab was given for additional six months in adjuvant settings along with an endocrine therapy. Primary endpoint here was pathological complete response and event free survival. So what did this study exactly show? Speaker 3 Well, I I think that you know our primary endpoint here was really PCR and this is significant because we typically don't think about our patients with ER positive breast cancer having very high PCR rates, right. We expect that with triple negative her two and we typically don't think about our ER positive patients being the patients that we're really thinking about immunotherapy for. And what we saw in this study is when we take high risk ER positive, everybody's grade 3, they're node positive or if they're node negative, they have large tumors that we saw an improvement in pathologic complete response rate from 15.6 up to about 1/4 of patients. So you know about a nine percent improvement. And you know certainly PCR isn't the end game here. It's really event free survival, you know essentially translating more patients to cure and we don't have that data yet, but to see an improvement of almost 10% in PCR rates where we think that's really hard to get an ER positive breast cancer I think was really thought provoking. Speaker 2 Erica, thanks for touching on the PCR and EFS as our primary at points, something that we continue to struggle with not only in breast cancer, we'll bring this up again in Keno 522 but also in lung cancer. How much is adjuvant component adding here? Is PCR the right end point to say maybe these patients should not be over treated. Any thoughts on using PCR to dictate our adjuvant treatment here? Speaker 3 Yeah, you know PCR isn't perfect, right, but it is a really good surrogate. We know that patients that have a pathologic complete response particularly in triple negative or her two positive disease, those are our patients that are less likely to relapse. Every curve we look at across breast cancer, those patients with a residual disease are always higher risk than those patients that don't. So you're right, it's not perfect, but you know PCR we really can get this endpoint a lot quicker than maybe relapse where particularly an ER positive disease, you know this could be 5/10/15, twenty years down the road. So you know that's a little bit of a tougher population and certainly one we have to follow over time and trials. The other caveat and the reason PCR was the primary endpoint here, there were actually two of these trials with immunotherapy for ER positive and the neoadjuvant setting is because of the CDK 46 debate. When these trials were initially designed CDK 4 sixes weren't standard of care for high risk patients. You know it like a bit of Cyclib and maybe soon Natalie with ribocyclib and so we can't give CDK with immunotherapy. And so really you know they were kind of dropping out this adjuvant component in one of these trials and trying to get an endpoint that could be done in the modern 2023 world where some of these high risk patients were going to go on to receive CDK. Speaker 1 Thanks for bringing that up and that's exactly what segues to the next conversation here because it is important that these trials were not designed to cover adjuvant abema CYCLIB now when you combine the immunotherapy with. Adjuvant approach where we would consider immunotherapy neo adjuvant while we see monarchy with persistent DFS benefit. How would you take this if this was to get FDA approved? Speaker 3 Yeah, I think that's a great question. I would really be thinking about using it as the neo adjuvant component. You know we've been talking about Keynote 522 and triple negative and well you know somebody that has APCR. Do we need to continue the pembro? I think for ear positive this would probably be with the chemotherapy. They go to surgery and then after if they qualified for CDK 46 really because of the profound benefit we're seeing particularly with the Mercyclob with long follow up in the adjuvant setting, I'd be thinking about giving these patients adjuvant CDK 46. You know there was an update of MONARCH E at ESMO and essentially with follow up of a 4 1/2 years, the benefit from adjuvant abemacyclob has increased to almost 8%. And essentially 7% of this was distant recurrence free survival. So truly translating patients to cure. And so I think we'd really be having to heavily think about CDK. There was also a little bit of updated data around Natalie with adjuvant ribocyclib, not FDA approved yet, but looking at some of the subsets, looking at patients that were stage two versus stage 3 or no negative versus no positive. And the benefit really looked across these groups, which reassured somebody for me because what I was asking myself is OK, well that's great that more patients may be eligible for ribocyclib, but how much benefit is a no negative patient really getting. And so I thought that was encouraging. So hopefully we see more of this. Speaker 2 And subsequent follow up, absolutely right now in adjuvant settings, CDK 4/6 in high risk remains the standard of care and hopefully from Natalie we'll have a broader indication in this adjuvant settings. TROPION-Breast01: Dato-DXd in Metastatic HR+ Breast Cancer So now if the same disease was to progress in metastatic settings, we have early data from Tropion Breasta one another phase three study looking at a new antibody drug. Conjugate dado DXD in patients that are hormone receptor positive her two new negative and have been previously treated with one to two lines of chemotherapy. Erica, your take care. Speaker 3 Yeah. You know, I think I'm mentally you can kind of file this in a substitute for chemo bucket, right. So these patients are hormone receptor positive in their tumor. They've exhausted their endocrine therapies and they've received one to two chemotherapy. So kind of second to third line in the chemotherapy? You know this is a trope 2 targeting ADC. So we have Sassetusumab, Gavitekin, Trodelvy, FDA approved in this setting and this is the more the trastuzumab derostocan backbone. So it has the Derostocan payload and what we saw as I think what we expected, we saw an improvement and progression free survival of two months, 4.9 up to 6.9 months and also a quite a large improvement in response rate. So you know really almost a 15% improvement in the percentage of patients that may have their tumor shrink. It's really interesting because although both sassetuzumab and Dado DXD are Trop 2 targeting antibody drug conjugates, they also have really different side effect profiles. We know that Dado we can struggle with stomatitis and sores in the mouth that can be difficult if it happens. We know with sassetuzumab we struggle a lot with counts. We also struggle with diarrhea and sometimes, particularly in the community, the counts can be problematic because it needs to be given on both day one and day 8. And so at least for me, sometimes my patients are coming in on day eight and their counts are too low to treat. So you know, not approved yet, but this may be a second trope to antibody drug conjugate in this space. Speaker 1 Well, the class of drug that you stressed as antibody drug conjugate is and it is something that we all need to get familiarize ourselves with especially in this particular space. At this conference, we saw this similar drug being utilized in lung cancer as well Erica. This is where I would rather prescribe Sassitusumab today as we discussed and if the disease was truly her two negative that was the case then if. PDXD was to consider that would be only in her two low settings. What are you planning to do in your practice if this was to get approved? Speaker 3 Yeah, I think sequencing is a big question, right. You know with our currently approved agents in triple negative space, our data is a little bit stronger with sassetuzumab. Remember in the DBO 4 the her two low trial that there were actually very few patients that had a true triple negative disease compared to the vast majority having hormone receptor positive disease. But you're right that, you know these drugs span across multiple subtypes, triple, negative, HR positive, etcetera. And realistically, you know I probably want to use both of these before I think about more chemotherapy. It seems like right now, particularly in the breast world that every antibody drug conjugate we look at is easily beating chemotherapy. We don't have a lot of data for sequencing. You know, it looks like from some kind of preliminary data at ASCO that may be changing targets. Speaker 2 Is more important than changing payload, but I think we are going to be sequencing antibody drug conjugates and I think the decision with the individual patient of which one to use first, which one to use second in the absence of any great data really kind of comes down to magnitude of benefit and also side effect profile, very true talking about side effect profile, another unique toxicity that was seen with DADO DXD was also dry eyes. So ocular toxicity is something that we really need to start getting a little more familiar with another ADC that we'll be covering for Gu and for two maps, the skin toxicities. With this new class of drug, we just need to get very comfortable with the supportive care as well. Keynote 522 Update: TNBC Standard of Care All right, switching gears and now looking at triple negative breast cancer, our current standard of care is to consider pembrolizumab and chemotherapy regardless of the PDL one score in stage two and above and then continue with pembrolizumab in adjuvant settings. Very similar approach to what we've discussed earlier for Keynote 756. Erica, your take on the update on EFS here. Speaker 3 Yeah, I think that this is really important because remember that you know PCR we feel very comfortable with and triple negative breast cancer. But ultimately you know, I don't, I don't think we really care from you know, an immediate patient standpoint of was there 2 millimeters of residual disease or was there not. Why we care about it so much is that we know when patients have PCR they're more likely to have good outcomes. So we're extrapolating that to event free survival. And So what we see here now you know at 39 months follow up our spread was essentially 76.8% to 84.5 with the addition of pembrolizumab and now with follow up at 63 months this has widened even a little bit further, 72.3% up to 81.3%. And I'll also just kind of point out another caveat here. You know, what stood out to me on this graph is that, you know this is really an intensive regimen, right. I mean, we're getting 4 chemo agents, patients are getting pembrolizumab. It's essentially six months of chemo. And for patients that don't have a pathologic complete response even at this, you know shorter follow up, 1/4 of our patients have already relapsed. So it really tells me that we still have further to go and triple negative, but definitely that primrolizumab should be considered for anybody that would qualify. And remember, it's actually very easy to remember. Unlike a lot of our other trials, it's tumor size of at least 2 centimeters or node positivity. Speaker 1 That is important that path CR can be or rather more commonly achieved in triple negative. And now seeing that EFS benefit really reiterates the current standard of care with chemo IO regardless of PDL one score in early triple negative breast cancer. Key Takeaways from ESMO 2023 Breast Cancer Erica, thank you so much for joining us today for our listeners. Stay tuned for a quick wrap up. Speaker 3 Thank you. Speaker 1 We've covered three important studies with Doctor Erica Hamilton and Breast cancer post ESMO 2023. Use of immunotherapy in early hormone receptor breast cancer looks promising with better pathological response, but we need more data to incorporate this in our daily practice. Speaker 2 Then we also covered Tropion breast of one study looking at DADO DXD in metastatic hormone receptor breast cancer. We do not have overall survival benefit yet, but if we do, this could be another option in endocrine resistant disease. This is the same agent that was also looked at in metastatic non small cell lung cancer. Speaker 1 To finish, we also discussed the update for KEYNOTE 5 two study which confirms the current standard of care with chemo immunotherapy in triple negative breast cancer patient population with EFS. And pathological complete response benefit look out for highlights for Lung Gu and GIS MO 2023. We are the oncology brothers.