Breast Cancer ESMO 2024 Highlights: Key Studies Discussed NATALEE, KEYNOTE 522, DESTINY-Breast12

Intro Hello, and welcome back to the Oncology Brothers Podcast. I'm Rahul Gosain, and I'm here with my brother and Co host, Rohit Gosain. This time, we're excited to bring you the highlights from the ESMO 2024 focused on breast cancer. Thousands of abstracts were presented here, but we've picked three key studies that can impact our current practice in the community. To guide us through this data. We're thrilled to have none other than Doctor Paolo Tarantino from the Dana Farber Cancer Institute. Paulo, thank you so much for joining us. Speaker 2 Hello Rahul, Hello Rahi. It's such a pleasure to join you and discuss this abstract. Speaker 3 Well, thanks so much for joining us from Italy. Polo, another exciting ESMO in the books here. We'll start off with focusing on three important abstracts from ESMO 2024 in breast cancer space. First of all, Natalie trial, we mainly updated results which recently just got FDA approved based on of this study as well. Then we'll dive into another standard of care practice which is Keynote 522 perioperative pembrolismab approach in triple negative breast cancer. And lastly, we'll touch on intracranial activity of TDXD based on Destiny Breast 12 study. Let's start off the first one Natalie trial. Natalie Trial Before we dive into any further, let's talk about bit about the study design. It is slightly different than Monarch E bit which was based on a bemocyclib in adjuvant setting. Speaker 2 Absolutely. Just like Marquee, this was a phase three trial basically trying to show if utilizing a CDK 46 inhibitor in the adjuvant setting rather than in the metastatic setting, we could actually prevent some recurrences, improve outcomes in patients with early stage no metastatic or more such a positive or to negative breast cancer. And but differently from monarchy, Natalie included a different agent, of course, ribocyclib combined with an aromatous inhibitor, whereas in monarchy you could have either an aromatous inhibitor or tamoxifen. Natalie included a much broader population because monarchy was restricted to not positive patients. Whereas in Natalie you have both patients with not positive disease or also high risk, not negative disease, high risk defined as grade 3 or grade 2 and a high evidence of high risk based on CI 67 or Oncotype DX. And interestingly, the the dose that was chosen for Natalie of ribocyclic is lower than the one that uses utilized in the metastatic setting most likely to to reduce the the risk side effects with adjuvant ribocyclic. Finally, I will mention one more important difference. Monarchy utilized adjuvant abemocyclic for two years whereas Natalie adjuvant ribocyclic is given for three years. So all in that basically Natalie was assessing the fear of a reduced dose of rivocyclib. Added venomous inhibitor can improve outcomes in patients with ear positive to negative breast cancer, with the primary endpoint being invasive disease free survival. Speaker 1 Paulo, thank you so much for laying that foundation because now we do have these two drugs available. Rohit, you mentioned ribocyclib was literally approved days after the data was presented at Asthma 2024 where we saw improved invasive disease free survival. Ribocyclib and aromatase inhibitors Paulo, can you walk us through what did we see at that four year mark and importantly, what does it really mean for our patients? Are you going to offer this to all your patients that are no negative? What about the patients that qualify for both RIBO and ABEMA if you have no positive disease? Speaker 2 Absolutely. It was so interesting to see such a fast approval. Well expected somewhat because the data we saw at ESMA was very nice. And in truth, we knew already that statistically Rajiv rebocyclic improved invasive disease free survival. But at this update of the date after 40, after yeah, 40 years, basically what we wanted to see is if there is a carryover effect after of the patients had discontinued adjuvant RIBO. And that's the case because it did update all the patient that either completed or discontinued adjuvant ribocyclib. And also we wanted to see what was the delta of benefit in patients that received RIBO compared to those that did not receive ribo. And basically we saw that at four years there was a delta of about 5% in invasive disease free survival. So what you see that at four years 88.5% of the patient that received Ribo compared only 83.6% that did not receive rival were free from mostly a recurrence. The IDFS event includes other events, but these were most of the recurrences. And when we looked at distant disease free survival, you see that most of these were distant recurrences, metastatic recurrences. And so we know that preventing those can really have an impact on patient's survival. And and This is why we expect that this 5% delta in invasive disease free survival very similar. There's the in disease distance to survival will in the long run translate in more patients being cured from their disease and having improved survival. But in order to to see an overall survival advantage, we have to wait a very long time. And This is why the FDA has approved this drug. And I think it makes sense to utilize this drug in clinical practice. Although of course, as you mentioned there are two drugs not proving this setting and should have been cyclic. The MARQUEE trial as a longer follow up has got more years of follow up after all patients have discontinued the drug and so I personally tend still to prefer the use of abdomicycly being patients that have overlapping indication. Although rebocyclic has a different toxicity profile and can be also be considered, but for patients with high risk, not negative disease, I do feel that considering ribocyclic is of course a good option. Whereas abemaciclib was never tested in non negative patients. So I would only consider ribocyclic in those patients. It does of course remain an agent with some risk of side effects. We know there are some epidotoxicity, the risk of side effect and also you can have cardiac toxicity in about 5% of the patients. And also on the long run we know they can also have financial toxicities. And so it's important to to discuss this important data, but also to, to understand all of this potential risk and always calculate the risk benefit ratio and, and, and make up for shared decision making with the patient when you decide about adjuvant CD case. Speaker 3 Exciting times with two FDA approved options now in adjuvant setting, abemaciclib and ribocyclib. As you stated ribocyclib slightly broader inclusion criteria there in comparison to Obama. ABEMA in general has more mature data important to address that three years versus 2 years distinction as well. Now moving on to another standard of care practice that we have been utilizing based off of Keynote 522IN triple negative breast cancer setting. Similar has been seen in lung cancer space where we have been utilizing perioperative immunotherapy and recently at Asthma 2024 at Presidential debate, Doctor Powell's presented Niagara study which is with Duraluma perioperative and bladder setting. At ESMO 2024, focusing on Keynote 522, we did see overall survival results. Before we discuss, it is important to acknowledge that this regimen is generally toxic. How to Administer Keynote 522 Paulo, there are different ways to administer this. How do you go about administering? I know AC can be given first or even carboplatin weekly versus 3 weeks. How do you go about administering this regimen? Speaker 2 So, yeah, I couldn't agree more with everything that you said. Meaning that, you know, the Keynote 522, we tend to call it this way just because there's so many drugs in it that if you want to call all of them, it takes a long time. You know, this includes 4 chemotherapy drugs plus an immunotherapy drug. And it's an intense regimen. And whenever you start this regimen, you may expect, you should expect side effects. Also some we saw some real world data showing that hospitalizations are not frequent in this case. But after showing the benefit of this regimen, we just know how important it is and how it can really save lives. And so it's important to administer it in the right way and there is no single right way because there is for instance, as you mentioned the sequencing, you can decide to start with dentrocyclins or carboplatin paclitaxel. Usually I start with carboplatin paclitaxel like in the study. And also you can see that the site is to administer the antral cyclins in a dose dense fashion or known don't dense in the trial. This was not done the those dentist administration, but we know that there is trials, there is large meta analysis suggesting the benefit for those dents. So I think either are reasonable. At data Harbor we tend to prefer the dose dents which creates some difficulties with matching it with the pamper infusions. But in the end all of this still is feasible and makes sense. The most important thing to remember is that when you add the immunotherapy drug, especially when you add it upon all of this chemotherapy drugs, you may expect immunotherapy related side effects, immune related side effects. It's important to recognize them and to stop immunotherapy and to give steroids whenever this happen and of course stick to the guidelines. But with that said, once again, we realize of how important this regimen is and not only in patients with not positive triple negative disease, but we even saw data dissected for patients with T2 and 0 triple negative breast cancer. There is a large population and there was a major benefit in that population. So most of the patients with early stage triple negative breast cancer nowadays qualify for this regimen. And it's important that the curve of learning of how to administrate is very important because once again, it can save lives. Speaker 1 Absolutely. And to be honest, when it comes to immunotherapy as a generalist or community oncologist, this is not just breast cancer. Immunotherapy in other cancers What I've mentioned, we're seeing this across different disease sites. And Paula, you mentioned those stents AC, there are times when I'm using that, I tend to switch my Pembroke to every six weeks as well to see if I can line that up right. Well, coming back to the toxicity, we saw that the rate of discontinuation of this combination even in the trial was close to 20 to 25%. So in the real world analysis, if anything, it's a little higher, not less than that. But the reason for us to give this toxic tough regimen, Paula, you touched on it is because it is saving lives. The benefits of the combination Initially we were seeing increased pathological complete response, but thankfully this has translated in an overall survival benefit. So, Paula, what did we see at Asthma 2024 for this study? Speaker 2 So what did we know before and we knew that the addition of pembro to Neurge and chemo and continuation of pembro after surgery were associated with the relevant improvement in event free survival. And that's relevant improvement. Now with longer follow up, a medium for up of 75 months almost further reinforced. What we see is that now we have a 9% delta in event free survival at five years without the ratio of 0.65. And also most importantly we saw that there is an improvement in overall survival. There is a delta of 5% in overall survival at five years, which means really we are not only preventing this recurrences but once again even improving long term survival. We do very similar as a ratio between event free survival and overall survival. Basically we are reducing by 1/3 risk of recurrence, we are reducing by 1/3 the risk of that which is very striking. And as we had seen previously with event free survival. Then there was this nice dissection of outcomes based on achievement of pathologic complete response or not at surgery. And what we saw is that the other ratio was quite similar among patients with pat CR, non pass CR. But we know that patients that achieve pathology complete response, very low risk of recurrence, about 5% even just with chemotherapy. And so most of the benefit with immunotherapy, we see it in patients with residual disease surgery. But in truth, we know that we cannot make, it's very hard to make this prediction ahead before starting your adjuvant treatment because you never, you're never going to know at that point if the patient's got to respond or not. And so right now, I feel that it's still reasonable to utilize chemo immunotherapy in all of these patients things upfront. But I do hope in the in the future, we're going to get better at predicting which patients may just receive chemotherapy and which patients really require the addition of embrylizumab or immunotherapy in general. And for that, we're really awaiting for more translational biomarker data from Keynote 5 to 2. And I do hope that in the future, we're going to see those data in some upcoming Congress. Speaker 3 Right. And as you stated, Paolo, that the role of pembrolizumab in adjuvant setting with when you actually receive PAT CR is questionable. Yes, we are utilizing it, but we will find out how the trials play out in near future. Now focusing on her 2 positive space, which is trastuzumab Duruxican, the talk of the town, it also has intracranial activity. Intracranial activity of TDXD Paolo, can you please touch on the study design and it's findings here please? Speaker 2 So I really feel that CDXD that the introduction of TDXD has changed the way we treat breast cancer and many other cancer. This drug is really incredibly active and I think one of the major perks of this drug is its intracranial activity. We had sensed this in breast oncology from several small trials that to see the trial, the Deborah trial, Rosette and many other either studies or real world experiences. But in truth, we still DNF a large active trials showing the intracranial activity of TDXT. Now finally we do have one and this trial was a Destiny Breast 12 that was presented by Nensoline at Esmorton in Barcelona and concomitantly published on Nature Medicine. And basically this was a post approval trial, Phase 3B four trial looking at TDXT among patients with her 2 positive metastatic breast cancer either with rheumatosis or without. There were two cohorts patients needed to receive less than two lines of prior therapy in the metastatic setting. And most of the patients, 50% of them had received one prior line, but 40% two prior lines. So this was a second third line trial utilizing PDXD for her to positive metastatic breast cancer. And and the primary endpoint was progression free survival among patients with baseline brain metastasis or response rate in patients without brain metastasis. And I do feel that the results from this trial was striking because among patients with baseline brain metastasis, we saw that more than 1:30 year from starting TDXT were free from recurrence. The medium PFS was 17.3 months. Once again, so striking this, we're talking here basically about a one year and a half of Disease Control in patients with very high risk disease brain metastasis at baseline. And when you look also at overall survival among these patients, it was basically super important possible between patients with baseline brain meds or not no brain meds, really thinking that this drug we can change the trajectory of patients with brain meds closer to those without brain meds. And finally, the response rate of TDXT industry intracranial response rate was 70%. Speaker 1 This is so, so, so exciting. And importantly, it's so good to see more and more clinical trials including our patients with brain meds Twallow now we have data from to catanet based regimens, be it with TDM one or Cape site to be and trastuzumab after Destiny best 12. If no contraindications to either of these regiments, what's going to be your preferred second line option, with or without brain mats? Speaker 2 And I ran a poll and I found that basically Twitter kind of things like me meaning that looking at this data you cannot help but think that TDXT further reinforced each role in second line for her to positive disease. And so the wide majority of the cases of patients with or without brain metastasis, I think trustee some of the rostic and would make the most reasonable choice in the second line. And in the future we'll see based on Destiny breast 09, if also in the first line. And I will mention that this data also reinforce, of course, this trial was only for patients that are to positive metastasized breast cancer. But we know that TDXC is also approved for her to low metastatic breast cancer and there may be an approval soon for her to ultra low her to zero with minimal her to staining. We have some data from some trials from the Daisy trial, the Deborah trial showing intracranial activity also in patients with her to low disease. And it totally makes sense. The response rate seems to be even in her to low disease, very similar in patients with or without brain mass. And so I feel that we're feeling more and more confident of utilizing this drug irrespective of her to status and irrespective of the presence or absence of brain metastasis. Speaker 3 Doctor Tarantino, thank you so much for sharing your thoughts around these key abstract from ESMO 2024 or for our listeners, let us go over a quick recap. Speaker 1 In this discussion we've covered 3 breast cancer studies with Doctor Paulo Tarantino that were presented at ESMO 2024, starting off with the Natalie trial which showed that adding Ribocyclip to endocrine therapy improved invasive disease free survival including in no negative patients. But this comes at a cost of added side effects of Ribocyclib for three years. Ribocyclib was approved on September 17th, 2024 for this indication. Then we also had a chance to touch on keynote 5 to 2 and update demonstrating overall survival benefit with periop, pembrolizumab and new adjuvant chemotherapy and early stage triple negative breast cancer. This continues to remain our current standard of care. Speaker 3 Finally, the Destiny Breast well showed promising intracranial activity with trastuzumab duruxigant in her two positive breast cancer patients with brain metastases. These studies continue to refine our approach to breast cancer treatment, offering new options and hope for our patients. Thank you for tuning in. Make sure to check out our GI Long and Gus MO conference highlights and discussions around the current standard of care. We are the oncology brothers.