HER2+ SABCS 2025 Highlights DESTINY Breast-05/Breast-11, HER2CLIMB-05, PATINA: Dr. Harold Burstein

SABCS 2025 HER2+ Updates and DESTINY Breast-11 Good afternoon everyone. I'm Rahul Ghosain here with my brother and your Co host Rohit Ghosain, 2 practicing community medical oncologist and we are the oncology brothers. Today we're diving into her 2 positive breast cancer highlights from SABCS 2025. There was a ton of exciting updates and new data, but we've handpicked a few key studies that are most likely to impact their practice. Speaker 2 Absolutely, Rahul. There's a lot going on in her two positive space and we plan to touch on DB11 and DBO 5 updates which were initially presented at ESMO 2025. Following that, we'll cover her two climb O 5 and closing off with patina child. This is all when we recently just saw TDXD with pertussumab got approved in frontline settings for metastatic her 2 positive breast cancer. To help us unpack all of this, we are excited to have Doctor Hal Burstein from Dana Farber Cancer Institute. Hal, thanks so much for joining us. What a phenomenal year for her two positive disease. Speaker 3 It's been a big year for breast cancer and I'm very happy to be with you today. Speaker 1 Hal, welcome. Let's jump right in with the early stage, her 2 positive disease initially at ESMO and now at SABCS. We're seeing data from Destiny Breast 11 in neoadjuvant settings. Can you please touch in the study designs and its findings and importantly who would be that right patient in your clinic today that will potentially get this over TCHV? Speaker 3 Sure, there've been so many studies with TDXD and her 2 positive disease, it's easy to miss the forest for the trees. This is the most active drug as a single agent that we have in her two driven breast cancer and it was initially indicated in refractory disease. Then it moved up to second line therapy when a randomized study showed that in the metastatic setting TDXD outperformed TDM one. And then it moved up to first line where we have the DBO 9 trial where it in combination with pretuzumab show that it would achieve the longer progression free survival than with the THP regimen. And now we're seeing it move into the early stage setting with this trial and the Destiny Breast O 5 trial. So you know it's really climbed the ladder in a remarkably short period of time. Every patient who has high risk her 2 positive breast cancer is going to get exposed to TDXD at some point in their treatment unless they get a non TDXD based neoadjuvant regimen and have a pathologic complete response. So you know it's been a very effective drug. If you go back to the schema side, they're just a couple of things important to note. The 1st is this was actually a three arm trial and the TDXD arm without the follow up of the traditional chemotherapy. Trastizumab was not reported upon but was said to be inferior. So monotherapy with TDXD, not adequate. The second point to be made is that the regimen that was served as the control arm was the anthracycline regimen followed by THP. Now any of your audience who's listening to the United States, who's given AC for her two positive breast cancer in the past five years, please raise your hand because there haven't been a lot. Our standard has been TCHP. That is not the global standard. This was a large international trial. They included it here, but it included only four cycles of the THP versus what would be 8 cycles of the combined anti her two therapy if you gave the arm here in green, which is the TDXT followed by THP. And none of this is standard for what we really do, which is TCHP for six cycles or 18 weeks of treatment. So I think that the design here is not wrong, but you do have to ask, is there still a reason to think it's better than some of the existing regiments that we use? What did we learn in this trial? We learned that the TDXD plus THP arm 8 cycles of that collective regimen outperformed dose dense AC followed by THP by way of pathologic complete response. So that's important to know obviously and it is a non anthracycline based regimen. I think it's still a little unclear who needs the neoadjuvant phase of the TDXD versus our existing options and that's because of the second study you're going to be speaking about which is the DBO 5 trial. If you look at the toxicity experience here, which you've thoughtfully just showed, there is more GI side effects actually then you see with even AC based chemotherapy, there were relatively comparable bouts of neutropenia. The neuropathy issues were actually more pronounced in the lower grade. There's the persistent risk of potentially serious pneumonitis with the TDXD drug. In this particular study, the numbers were pretty comparable with anthracycline based regimen. So you know, it's not that it wasn't active, but whether it really warrants priority as the neoadjuvant treatment of choice is still debatable. Speaker 2 Well, thanks so much for covering all that. What you brought up was the dose dense AC in her two positive space. That is exactly right. We don't use that here in USA. I did not raise my hand. But again it does get utilized here globally though given this data at hand where we are seeing impressive PAT CR rates and TDXD and with regards to now the Destiny breast O 5 where high risk residual disease, we are seeing TDXD being tested here. DESTINY Breast-05: TDXD for High-Risk Residual Disease What are we seeing here? And if this was to get approved in an adjuvant setting, what are we doing here? Speaker 3 So to my mind, the Destiny breast O 5 is more overtly a practice defining study. And I say that because it's a population that is patients who had her 2 positive breast cancer who received a standard chemotherapy, trestuzumab, pertuzumab based regimen and still had high risk residual disease with disease leftover in the lymph nodes or had presented with a higher stage of cancer like T4 tumors, an extensive nodal involvement and again still had residual disease. The point is that our standard has been well defined since the Catherine study was first reported close to a decade ago. We know that TDM one is an important drug here and as it was shown in the metastatic setting, what we learned in DBO 5 is the TDXD in this cohort of patients, residual disease clearly outperformed the TDM. One option and what you can see as you've kindly shown here is that the disease free survivals differed by close to 8%. In patients who had anthracycline based regimens, it differed by 10%. In patients who had platinum based regimens, it was still a difference of 6%. And I think that point about the adequacy of the Anthracycline speaks to what we were just talking about, that maybe this isn't really the best regimen. So clearly an improvement in outcomes and I think a very rational use of the TDXD. There are patients who are going to get pneumonitis and ILD from the Destiny Breast O 5 treatments, but we've really focused on a group here that's at higher risk for recurrence where they didn't have an adequate response to the antibodies plus chemotherapy. And I'm already moving patients towards the TDXT regimen. I think it's a very practice defining trial. Speaker 1 To me this data in adjuvant settings for very high risk patient is more convincing. And a few things to keep in mind, this is not just all comers with residual disease like what we see with Catherine trial. This was preselected very high risk disease. The other thing to keep in mind when we're talking about TDM, one with Katherine trial in our current standard of care, we're often not doing these periodic scans here. If TDXC is what we rely on, we do have to do these periodic scans to look out for ILD. Despite that we were looking for ILD. But you're also technically screening for any progressive disease. Even then we saw TDXD do better. This to me is practice changing for that very high risk patient. Speaker 3 That's an interesting point. So your argument is that the scans in the TDXD arm actually bias against the drug in the sense that you're monitoring more vigorously for metastatic occurrence and yet it's still clearly outperformed. I hadn't quite put that together, but I think that's an excellent point. Speaker 1 Yeah. Upfront, telling our patients that given that TDXD is on board, we should be looking for ILD. But on our end, we're also monitoring the disease. Speaker 3 So a really moving question is can you start to do some modeling and figure out if you achieve a path CR with existing drugs, you're good. Is that rate high enough that salvaging the residual disease patients with TDXD makes sense? It'll be very interesting to see how those discussions evolve. Speaker 1 Absolutely and again here at SA BCS that update in invasive disease free survival to me is very convincing. I. Speaker 2 Agree. Speaker 1 All right, on to metastatic disease. Just a few days ago, Roy, as you brought up, TDXD with pertuzumab was approved in frontline settings for metastatic her 2 positive disease here at SA BCS we also saw data on her two Climo 5. HER2CLIMB-05: Maintenance Strategies for Metastatic HER2+ How can you go through this study and its findings? This will also likely get approved in the near future. So at it again, who would be that right patient for this regimen over TDXC and pertuzumab? Speaker 3 So I want to take a step back and say what we do in clinical practice. So what we've done in clinical practice for her two positive metastatic disease for a long time has been to offer induction treatment with chemotherapy and trestuzumab and pertuzumab. And then after some interval of time, usually it's about four to six months, maybe a little longer, maybe a little less, the patients almost always have an excellent response. In those to achieve a very good response, we peel off the chemotherapy to spare them from the side effects and reintroduce endocrine therapy if the tumor is ER positive and her 2 positive. So there's never been, until this past 12 months, a study that really critically looked at this strategy. But we've all been doing this every day for the past 15 or 20 years. That's the context that's really important when you think about her to climb 05 and the patina study. So both of these studies were designed to actually explore rigorously the value of tweaking that maintenance phase of treatment. They shared a design of induction treatment with THP after response or in some instances without progression. They then randomized patients to the maintenance phase of HP or in this study Kurtuklimo 2HP plus the tecatinib. And what they showed here was that by introducing to catnip, the small molecule tyrosine kinase inhibitor, they were able to extend the progression free survival. And what you'll notice when you look at these curves is that there was a pretty robust difference. The difference is on the order of eight to 10 months. I think a benefit that is a nice way of really sparing people the chemotherapy. We'll come back to the overall survival discussion in a moment. I think the other key piece here is that if you look at the outcomes by hormone receptor status on your right hand figure, there's clearly more of a signal of benefit in the ER negatives than in the ER positive cancers. The key point really to think about is what does the survival data show because everyone in the US would have access again to to catnip in a second or third line setting already. It's FDA approved in combination with capsidamine plus trastuzumab. When you see a survival difference here, you have to wonder, is it because the drug is so potent or is it because in an international study, patients do not have access to good second, third line her two directed therapies. This is a growing problem in the metastatic breast cancer where we now have so many new drugs, the CDK 46 inhibitors, the oral surds, the targeted therapies, the anti her two drugs that unless you're really making sure patients have full access to these drugs, you're both conducting a study that's not quite ethical. And secondly, can be misleading when you're interpreting overall survival if they don't have US benchmark standards. So I think you have to be cautious about interpreting the survival signal here. Did these patients get for instance TDI, the XD at progression, which would certainly be a standard in the USA? Speaker 1 Few things to dissect here, how thank you for touching on the availability of these drugs, not just here in the US, but globally also having the right comparator arm for us who really appreciate these differences out here in the US. How very likely we'll see this get approved and then we'll be making decisions between our current treatment option of THP or TDXD pertuzumab or her two climo 5. Do you have a particular patient in mind where you think that TDXD pertuzumab will likely do better over her two climo 5 in the community? Should we broadly adopt TDXD pertuzumab and then switch to maintenance after induction therapy? What would that look like in your clinical practice today? Speaker 3 So you know the related study here is Destiny Breast O 9, which actually really was a maintenance study if you think about it, because in Destiny Breast O 9, the arms were THP for about 6 cycles followed by HP. So it was a maintenance strategy versus continuous TDXD and pertuzumab and what was now FDA approved and what they showed is that the TDXD pertuzumab outperformed. I think this is where doctors and patients are going to have real conversations about how the patient is doing. I think for many people TDXD will become a first line option. It has a slightly higher response rate, though the response rates with both treatments were very high, close to 75 or 80%. It's going to depend on the tolerability profile. There are patients who really tolerate TDXD beautifully and the risk of interstitial lung disease is monitored for and remains sufficiently low. If you want to continue to have that very deep treatment response and prolonged progression free run, there are many patients who could use a break from the TDXD and I think it's going to be perfectly reasonable to induce and then switch over to a maintenance strategy and also incorporate endocrine therapy. My guess is that if you actually look at charts as opposed to talking heads experts, you're going to see that most of the time people get some induction regimen and then a maintenance because at some point years and years of TDXT becomes grueling and you can always reintroduce the drugs. Speaker 1 We'll get a chance to touch on her hormone receptor positive disease in a second. But when we're switching to maintenance settings here, is that going to be trustezmepratizumab or you're truly switching to trustezmepratizumab as we're trying to take some time off from heavy chemotherapy? Speaker 3 Well, the toucatinib, you know, it's an interesting drug. In my experience, there are some patients who tolerated beautifully and there are some patients who really have a lot of GI side effects. And remember we're talking about maintenance in patients who are essentially asymptomatic from their cancer. So it all comes down to how well they tolerate the drugs and there clearly was some diarrhea, increased risk with the tucatinib based regimen. I think for patients who have ER negative disease, it's probably worthwhile to introduce the tucatinib if they still have measurable disease and if they are tolerating the tucatinib well. But in patients who achieve near complete response, in patients where you're going to be able to get to 2nd and 3rd and 4th and 5th lines of therapy, I don't know that there has to be urgency to getting to the to catnip, especially if the patient's experiencing GI side effects. Speaker 2 Well, the side effects are certainly very important to tackle because of the fact that we have to consider that this is palliative intent, especially when multiple options are approved. We have to consider all these and patient shared decision making being the Center for this hell. Speaker 3 Sorry to interrupt me, but you know, look at the curves here. I know everyone will say tucatinib clearly makes it better, but there are patients who get trastuzumab without endocrine therapy because it's ER negative and without tucatinib, 30 to 40% of them are going three years without progression. So I mean, you know, they're going to get to the next line of therapy and a lot of people that will be very appropriate care still. Speaker 2 You know indeed hell we just talked about from her to climb O 5 as you stated that ER negative patients did relatively well when compared to ER positive disease space. PATINA Trial: Managing Triple-Positive Metastatic Breast Cancer Now let's dive into that particular space that is the triple positive disease. We first saw the data from SABCS 2024 patina trial. This was adapted quickly for ERPR positive and her 2 positive disease where THP upfront followed by palbociclib and endocrine therapy partnered up with dual anti her two therapy in the maintenance arm. This resulted close to about 15 months of median PFS. But now we also have TDXD and tagatinib as treatment options upfront here at SABC as we saw updated results around patina. Can you touch on the findings and what's going to be your practice for triple positive metastatic breast cancer and especially that aspect of CNS metastatic disease? Speaker 3 For sure. And I think one of the limitations of her two climb 05 is they did not uniformly get endocrine therapy in the ER positive her two negative cancers. Whereas in patina they got endocrine therapy with or without the addition of the CDK 46 inhibitor Palvis iclip. So if you look at the control arms for her two climb 05 in the ER positive group versus the patina patients did a lot better because endocrine therapy works in the setting of her 2 positive disease. There was another study at San Antonio that was called DETECT 5, right? But DETECT 5 they give chemotherapy trestezumab pertuzumab versus endocrine therapy with abema pertuzumab trestuzumab the endocrine arms did almost as well, if not as good as the chemo endocrine therapy in combination with anti. Her two treatment works nicely in her two positive breast cancer patina shows that well. Pelvic Cyclip is a readily tolerated drug and oncology and there was a meaningful extension of progression free survival. In the original reports it was on the order of almost 15 months without needing to reintroduce chemotherapy. At five years years, a third of the patients are still progression free on HP endocrine treatment. So think about that in the context of DBO 9. There is a group of patients who are going to do really well for a long time. Intriguingly, as you've shown in your left hand figure here, the incidence of CNS progression was slightly lower in the group that got Palbo plus endocrine therapy. Something that I'm not sure I would have guessed would be observed, but perhaps another reason for thinking about the Palbo in this context. Speaker 1 Coming back to these three options being available for that triple positive DBO 9 earth to climb O 5 patina, would you feel comfortable just with patina triple positive or would you still consider TDXC, pertuzumab induction and then moving forward with the endocrine therapy phase as maintenance? Speaker 2 And would that decision change if there is CNS Mets? Speaker 3 Good questions. If there's CNS Mets, we have good data that TDXD is an active drug. It also depends on what the patient's already seen. If this is a patient who had TCHP and was on trastuzumab based regimen and recurs 2 years later, well for sure you're going to go to the TDXD. As you guys know, in so many of these trials now 50 plus percent of the patients are de Novo her 2 positive disease. That's because of two things. Again, they're global trials, so they don't typically have screening mammography in these countries. So there's a lot of de Novo metastatic disease. And in the US where everyone gets aggressive anti her two treatment, it is not so common anymore to see recurrent her 2 positive breast cancer. So you're seeing more de Novo disease. I think that one way or the other, you're getting TDXD plus pertuzumab or THP, whichever you think is going to work best for your patient. You're going to use it for an induction chunk of time. And then assuming they've had a good response, you look at that curve on the right for the ER positives, 30 to 40%, five years of tumor control without overt progression. That looks pretty compelling. That's even without the POW bow. So it's a smorgasbord table. You get to go back as many times as you want to your favorites and there's lots of choices. But I think induction with all of these things, then maintenance. If it's your positive, you're adding endocrine therapy and considering Palbo. If it's your negative, you're considering the tacatinib. And this is a big step forward for her two positive disease. Again, we've been doing this, but it's sort of operationalizes it. Speaker 1 You know, making sure that our patients are getting exposed to the second and third line treatment options, coming back to that side effect profile and managing those. That is all what this is all about, how we've covered a lot here in a short amount of time. Thank you so much for sharing your thoughts around neoadjuvant and adjuvant TDXD from Destiny Breast 11 and O 5. This evolving metastatic landscape with PER 2 Climo 5 and the recent approval of TDXD and pertuzumab in frontline and how patina is going to fit into our clinical practice for our listeners. Key Takeaways and Future of HER2-Positive Treatment Before we close, let's do a quick recap. In this episode with Doctor Halberstein, we focused on her 2 positive breast cancer updates from SABCS 2025. We saw Destiny Breast 11 data on TDXD in new adjuvant settings with improved PCR and improved quality of life metrics reported by the patients than in adjuvant settings. Based off Destiny Breasto 5, we saw improved invasive disease free survival when compared to TDM one in high risk residual disease. Well, we also covered metastatic disease. Your thoughts there? Speaker 2 Rahul, be it an early disease or metastatic disease. Space ILD from TDXD is an important thing to consider, especially when there is mortality associated with it. However, we should not forget the other common side effects that come along with this. That is nausea, alopecia, fatigue. They're all tied up to common side effects from TDXD metastatic disease space. We saw improvement in PFS for roughly about 8 to 9 months with two Catnib in her two Climo 5 study. If this was to get approved, we'll have three potential options as you brought up to Doctor Burstein that will be THP followed by HP or adding to Catnib in maintenance phase based off her two Climo 5 or TDXD with pertuzumab based off recent Destiny Breasto Nine approval. And to close off, we touched on the PATINA trial where the triple positive disease in maintenance settings after the THP induction, palbo cyclib and endocrine therapy along with dual anti her two therapy in maintenance phase provided close to about 15 months of improvement in PFS. Patients with her two metastatic disease are living longer today because of these advances. Thanks so much for joining us. Check out our other episodes on treatment algorithm, recent approvals and more conference highlights. We are the oncology brothers.