SABCS 2024 Highlights - INSEMA, KEYNOTE-522, OlympiA

Intro Hello and welcome back to another episode of the Oncology Brothers podcast. I'm Roy Gosain and alongside with my brother and Co host Rahul Gosain. Today we are here to cover another highlights from San Antonio Breast Cancer Symposium 2024, focusing on three crucial studies, First one being in SEMA trial in hormone receptor positive space and then switching gears to Keynote 522 study and then ending off with an update from Olympia study. To cover all this, we are joined by Doctor Laura Hubbard from UCSF. Laura, it was so good to see you at San Antonio Breast Cancer. Thanks for joining us today. Speaker 2 Wonderful. Thank you so much for having me. Speaker 3 Laura, welcome. Let's dive right into this with our first study and summer study, which was also published in NEGM shortly after its presentation at SABCS. SEMA Trial So this particular study looks into the utility of axillary surgery when compared to axillary lymph node biopsy and early stage breast cancer. Even though our surgery colleagues face this question day in, day out, as a medical oncologist, it is still important for us to appreciate this landscape as well. Laura, can you touch on this study design and its findings? Speaker 2 Sure. Of course. So this was a really interesting study presented last week at San Antonio. And the key question is does every patient need a Sentinel lymph node biopsy? And so this trial was a large over 5000 patients randomized non inferiority study that compared the omission of Sentinel lymph node biopsy versus the use of Sentinel lymph node biopsy to evaluate whether omitting a axillary surgery compromised invasive disease free survival. And so as mentioned, very large study on patients had to have small tumors. So they had to be T1 or T2 and clinically node negative and patients were enrolled to either receive the Sentinel lymph node biopsy or not with the primary endpoint being invasive disease free survival. And at a median follow up of 6.1 years, what they saw was that there was no statistically significant difference and 91.7% invasive disease free survival in patients who received the Sentinel lymph node biopsy versus 91.9% in patients who did not. And there was also no difference in overall survival 96.9 with Sentinel lymph node biopsy, 98.2 without. And importantly, they also noted in the presentation and the publication that patients who skipped axillary surgery reported fewer complications, lower rates of lymphedema, better quality of life. So all kind of important, you know, clinical features for our patients that are kind of making this decision. They did see however, the axillary recurrence was slightly higher in the non surgery group, about 1% versus in the patients who received the Sentinel lymph node biopsy 0.3%. And they did kind of comment that these were patients who are undergoing breast conserving surgery, so they were getting radiation anyway. And so there was some thought that the radiation to the breast provided at least some incidental coverage to the axilla, which was kind of a point that was made as well. So I think, you know, what do we do with this data and kind of how do we interpret this data in the current landscape? I think this this trial enrolled a very specific patient population. I think they were patients who are 50 years and older who had a lower risk, you know, profile smaller tumors less than 2cm grade one or grade 2. So I think this is the population where you can consider, you know, applying this data. I think some of the caveats, however, I think the six year follow up is pretty good. However, we know that for these smaller low grade tumors, these tumors can recur out to 20 years. So we really do need longer follow up to know if this omission of Sentinel lymph node biopsy, you know, the IDFS translates to a no longer IDFS benefit with longer follow up as well. I think the other thing that I thought when I was hearing the state at San Antonio is, you know now we have the option to use adjuvant CDK 46 inhibitors in patients who are node positive. And so if a patient forgoes a Sentinel lymph node biopsy and they might have actually had a positive Sentinel lymph node, you know, are we missing an opportunity to consider treating that patient with, you know, adjuvant ribocyclib or adjuvant abemaciclib? I was digging through the New England Journal, about 14% of patients where they did do the Sentinel lymph node biopsy in this trial actually had a positive Sentinel lymph node. So you know about that rate, you know, 10 to 15% who we thought were clinically node negative, in fact were positive. And that would be a patient that I would, you know, certainly discuss, you know with the approval of ribocyclib now for even small tumors as long as they're node positive, it is a consideration. And so I think that kind of changes how I look at this data as well a bit. But nonetheless, I do think it's kind of great to have this option for some lower risk patients to consider the omission. I think just some caveats on the length of follow up and how it impacts adjuvant medical therapy that should also be discussed with our patients before we kind of consider adopting this data. Speaker 1 It's such a fine balance to sort of manage the quality of life aspects, but of course not compromising any of the future outcomes. And as you stated, this was something that was done prior to the era of CDK 46 inhibitors and now with ribocyclib being utilized in even node negative settings as well. So this definitely changes some of that. And of course, the longer term data will rather dictate where we are moving on. Laura, any portion like what portion of these patients were rather hormone receptor positive, HER 2 positive and triple negative? And would you think this sort of segment applies to early breast cancer throughout? Speaker 2 Yeah, really good point. So these are all hormone receptor positive, her two negative patients. And so I think, you know, I would be hesitant to adopt this across subtypes because it has wasn't how it was studied here. And I think even more important for the her 2 positive and triple negative subtypes to know their nodal status because that would dictate their, their therapy choices as well. So would be cautious there. Speaker 1 Well, certainly the theme what we saw from San Antonio and other conferences has been this de escalation especially without compromising some of the outcomes here moving along into the from early disease to rather triple negative slightly larger or lymph node involvement, which is keynote 522 more than 2cm and no positive disease where chemo IO has been the standard of care where perioperative approach of pembrolizumab. Pembrolizumab in early breast cancer However, we all continue to decide which is that population where we can de escalate rather adjuvant pembrolizumab or how to decide to who will is going to get these fine medications because they're extremely toxic. At San Antonio, we saw an update from Keynote 522 with regards to biomarker. Update from Keynote 522 with regards to biomarkers Laura, your thoughts here? Speaker 2 Yeah. So, you know, we've now been using Keynote, the Keynote 522 regimen for some time with, you know, great success. We saw the five year update of overall survival at ESMO showing a 4.9% improvement in overall survival using this regimen. I think the key question though is does everyone need the pembrolizumab? And we've previously seen the data that regardless of PDL one status, pembrolizumab was beneficial, which is why we don't check PDL one status before giving this regimen in the early stage. Whereas of course, in the metastatic setting, it does depend on their PDL 1 status. And so this abstract was basically looking at, you know, are there, you know, we know that PDL 1 is not the answer. Are there other biomarkers that might help us decide who needs pembro versus who doesn't? Because, you know, we don't want to give a medication where the patient is not, you know, allowed benefit, especially with the side effects associated with pembrolizumab. And so this abstract looked at the association between some exploratory biomarkers and PCR as well as event free survival in a number of kind of different combinations. And they found that several biomarkers were prognostic but not predictive of benefit with pembrolizumab. And that top graph that you see there shows that they looked at T cell inflamed an 18 gene expression profile and they saw that if patients did have this profile that was increased, it was associated with increased rates of PCR and EFS actually regardless of treatment arm. So whether or not pembro, they got pembro or placebo. So these patients had higher PCR and higher EFS sort of regardless Interestingly, TMB there's a tumor mutational burden was positively associated with higher PCR and higher EFS in the pembrolizumab arms, but but only associated with PCR and not EFS in the placebo arms. So you know, neither of these really seem to be that useful and distinguishing who needs pembro versus who doesn't. But sort of interesting correlations we're seeing kind of regardless of of treatment arm with those. And then the bottom graph shown there are looking at the associations with molecular subtypes and they looked at basil like immune activated, which is on the left basal like immune suppressed is the BLIS on the 2nd 1 / L AR is luminal androgen receptor. And then the MES is mesincamol. And these are basically all the tumor intrinsic molecular subtypes. And the question was, you know, are certain subtypes more likely to benefit from pembro versus not. And you can see on the bar graphs at the bottom across the subtypes, there were slight differences in response rates by, you know, whether or not someone received pembro or not. I think the most interesting 1 is in the luminal androgen receptor. There seemed to be an even more pronounced actual actually benefit with pembrolizumab compared to placebo in that group. But sort of regardless, the key take away is that across all of these subtypes, there did seem to be a benefit from pembro or you know, a kind of, you know, an English Englishable difference there. And so I wouldn't use these subtypes to kind of help decide who needs pembro or not. So I think the bottom line from this abstract, the fact is you know we did see some interesting trends, but nothing that clearly showed, you know, which patients would benefit from pembrolizumab versus not. And so there is no clear biomarker identified yet about who needs pembro in this setting. And so I would continue to use pembrolizumab kind of across all patients with stage 2 and stage 3 breast cancer who meet criteria per this trial and not use any specific biomarker to help make that decision at this time. Speaker 3 Absolutely. I think it's important for us to reiterate those practicing in clinical community settings. There's still no good predictive biomarker and anyone who falls in this inclusion criteria, Keno 5T2 still remains standard of care. Laura, you touched on overall survival. Overall survival benefit in patients who did not achieve a pathological complete response versus PCR Overall survival benefit was actually typed it better in patients who did not achieve pathological complete response versus PCR. That's the other thing that we've talked about. Can we use PCR as our marker? That is also not the case. Your thoughts there and the Keynote 522 regimen AC every three weeks versus dose dense AC. What's your practice? Speaker 2 Yeah, both great questions. So it's sort of interesting, you know, previously we thought that if you achieve PCR that usually translate to EFS benefit. And so we're using PCR as a surrogate marker for EFS, but with longer follow up. In the Keynote 522 trial, one sort of interesting thing that emerged is that even amongst patients who achieved PCR, those who got pembro actually had slightly better EFS than those who did not get pembro, even though they both got to PCR, which is a suggestion that maybe there is, you know, you know, EFS or PCR is not the end all be all that, you know, it is a surrogate biomarker and maybe pembro even beyond PCR is important to, you know, achieving better, reducing the risk of recurrence, which is ultimately what we care about, right? We want patients to not have recurrence of their triple negative breast cancer. And so suggesting maybe that not all PCR's are equivalent. I think these were sort of small differences, small numbers, I think hard to truly know if that's the case across all trials, but just emphasizes the point. I think that PFS or sorry, PCR is a surrogate biomarker that doesn't always equate to equivalent risks of recurrence, I think is sort of interesting. And then to your second question, you know, dose dense AC versus not, you know, at UCSF we do use dose dense AC. Dose-Dense AC vs. Not So we give it every two weeks and use growth factor to help support our patients. You know, there's a lot of debate about whether you need to use dose dents or not. And you know, there's some suggestion that possibly dose dents is more efficacious, although I think different trials have seen different outcomes there. But we do tend to use dose dents. The pembrolizumab of course is still given every three weeks, so it doesn't line up quite as nicely. And I think it is important to use growth factor to support patients getting dose stents to, you know, reduce the risk of neutropenia and febrile neutropenia in particular. But I think that is our practice. Speaker 3 Absolutely. In my practice when I've used dose stents AC, I've actually switched pembro to every six weeks. So it lines a little better in that settings. Laura, thanks. Yeah, thanks for touching on that. Now let's jump on another standard of care use of a lab prep apartment better in Braca positive patients. CPS plus EG for Braca Positive Patients This was approved based off Olympia study. And here we have an update on this study. Laura, can you touch on its initial study design and the recent updates? Speaker 2 Yes, absolutely. So the Olympia trial was a Phase 3 double-blind randomized trial that enrolled almost 2000 patients who had either hormone receptor positive, her two negative or triple negative breast cancer as well as a Braca one or Braca 2 pathogenic mutation. They also had to have high risk clinical features as shown here. If they were in the neoadjuvant group for triple negative, they could have a non PCR. If they were in the ER positive or PR positive, her two negative group, they had to meet this criteria with CPS plus, EG Honestly, I look it up every single time. It's hard to remember the the specific criteria there off the top of your head, but just remembering non PCR and meeting this high risk criteria that then you can look up the specifics of if patients were treated in the adjuvant setting. If they were triple negative, they had to be PT2 or PN1 and if they were ER or PR positive, they had to have four or more positive lymph nodes. So basically you know high risk patients in either of these groups were randomized 1 to one to receive either elaborate 300 milligrams twice daily for one year versus placebo twice daily for one year with the primary endpoint of invasive disease free survival. And this is the updated survival analysis at six years. And what we saw is that first looking at the IDFS, there was a 9.4% difference at six year IDFS, which is incredibly impressive. And you know, any drug that's receiving almost a 10% difference in IDFS is, is definitely, absolutely worth giving to our patients. So really important, you know, new advance for our patients to continue giving this drug in the adjuvant setting for those that meet criteria. And then we also saw an overall survival benefit. So this is the updated data at six years of 4.4% difference in overall survival, which is actually even more than we know. We'd previously seen the data for four years at 3.2 and the curves have only continued to separate with longer follow up. So now a 4.4% difference at six years. So I think this is really a practice affirming data. You know, we are already using olaparib in this setting and I think just even further emphasizes, you know how efficacious this drug is for our patients with Abraca 1 and Abraca 2 mutation. I think you know, several things that come up with this. I think number one in the triple negative setting, you know, how do we, you know, how should we combine this with pembro? Should we do Cape instead? You know, there's lots of different questions. I think my practice is is with the keynote five to two trial there was the adjuvant pembrolizumab given and we know there's safety data with pembrolizumab plus elaborate. And so even though neither study was studied exactly like that, my practice is if I give a patient the Keynote 5 to 2 regimen, they do not have APCR, but they do have a Bracha one or two mutation, I'll do pembro plus elaparib in that patient group and not give the capesitabine. If a patient doesn't have a pathogenic BRCA one or two mutation, then I combine capesitabine plus pembrolizumab. And so you'll kind of have those two different options. And I would preferentially use elaparib for patients with BRCA one or two mutations. Given this, you know, impressive benefit in IDFS and the overall survival benefit, I think the data is much stronger than the use of capesitabine. So it's certainly preferentially used elaparib in combination with pembro for these patients. And then I think for our hormone receptor positive patients that meet criteria, you know we have the option of CDK 46 inhibitors as well, right. So ribocyclib or abemaciclib, neither of which has yet demonstrated an overall survival benefit, whereas we do have an overall survival benefit here with elaparib. And so in that setting I actually also preferentially use elaparib in combination with endocrine therapy and I would give one year of elaparib combined with endocrine therapy. And then in the very highest risk patients, you know, I want to do everything I can to reduce their risk of recurrence. I'll sometimes even follow that with, you know, two years of Obama or three years of RIBO after you're done with the adjuvant lab. I wouldn't combine them, but you can kind of sequentially give one after the other. Again, not studied exactly like that in any particular study, but just trying to do everything we can for our highest risk patients to reduce their risk of recurrence. Speaker 1 Thanks for covering that, Laura. And that's extremely important. That's what our practice has been at least from community standpoint combining that is with pembrolizumab and triple negative breast cancer setting with the labyrinth. Just to reiterate the importance of the timeline here from Createc standpoint, Cape Slidabine is there for six months time, pembrolizumab from the start of like or initiation of therapy total of 1 year time. Labyrinth is one year time. When moving into the hormone receptors positive space. We have abemaciclib for two years while RIBO is for three years. Speaker 3 Yeah. And I think we're keeping the dose, keeping this timeline because this is all shifting and all these new approvals. We have to keep all this in mind. And again, as Olympia continues to show overall survival benefit, I think the other important part is making sure we offer germline testing for these patients so that they're exposed to these park inhibitors and importantly, these patients and their families get genetic counseling. I think that is very important. Laura, thank you so much for taking the time to walk us through these three important studies from SABC CS2024. For our listeners, let us go over a quick recap from today's discussion to recap. Recap Today's discussion with Doctor Laura Hubbard from UCSF. We've covered the Keynote 522 update on immunotherapy in triple negative breast cancer and Olympia trials, insight on adjuvant labyrinth for BRCA patients, and in summer study findings on possibly omitting axillary surgery in some breast cancer cases. Speaker 3 Unfortunately, we still do not have a good biomarker in selecting the right patient for KEYNOTE 522, which is our chemo immunotherapy and periop and ongoing post op immunotherapy. For now all comers with triple negative breast cancer that meet the inclusion criteria for the study. This remains the current standard of care. Then the Olympia trial reiterated the ongoing overall survival benefit from elapreb in patients with germline bracha driven disease. Lastly, as Rohit mentioned, based on INSEMO trial, we can forego axillary surgery in selected early hormone receptor positive breast cancer patients. Thanks for tuning in. We'll see you in the next episode. We are at the Oncology Brothers.