Trastuzumab deruxtecan (T-DXd) + Pertuzumab FDA Approval in Adv HER2 Breast Cancer: DESTINY-Breast09

Unpacking the DESTINY-Breast 09 Study Design and Findings You know we saw close to 50 new approvals and indications in the world of cancer in 2025. I don't expect 2026 being any different. But before we get carried away with all that is coming our way this year, in this discussion today we want to focus on trustezumab, durkstecan and pertuzumab, one of the recent FDA approvals in her two positive metastatic breast cancer. Hello everyone. I'm Rahul Ghosain and I'm here with my brother and your Co host Rohit Ghosain and we are the oncology brothers. Speaker 2 Right, Rahul, exciting times indeed with what we saw at DESTINY Breast 09 study was PFS improvement of 26.9 months to 40.7 months with hazard ratio of 0.56 or DBO 9, which led to the approval of TDXD plus pertuzumab. Here is clearly practice changing, but there's a lot happening in this space to make sense of what this means for us in clinic. We're excited to welcome back Doctor Sarah Tulaney, the lead author on the study and practicing breast medical colleges from Dana Farber Cancer Institute. Sarah, thanks so much for joining us. Speaker 3 Thank you guys for having me, I appreciate it. Speaker 1 Sarah, congratulations. Because of these efforts, our patients are indeed living longer. Let's dive into DBO 9. Can you walk us through the study design and its findings? Speaker 3 Yeah. This was a trial trying to understand if TDXD should have a role in the first line metastatic HER 2 positive setting. We've obviously seen very exciting data about with the use of TDXD in pretreated metastatic HER 2 positive disease. And I will just say for background purposes, we actually started designing Destiny Breast O 9 right after the findings from Destiny Breast O1 were reported. So this was after we had data for patients in the very pretreated setting getting TDXD monotherapy in a single arm study showing very impressive PFS, which made us wonder if it could be better than the first line Cleopatra regimen. And I say that because we didn't actually have results from Destiny Breast O3 when we to design this trial. Obviously Dusty Breasto 3 showed, you know, that PFS was almost four times as long compared to TDM one in a second line setting. And the PFS was, you know, about 29 months, much longer than we've ever seen with Cleopatra. So I think people thought it was very likely that TDXD would have a role in the first line setting, but we didn't actually know that. And I say that because one could argue why design the trial by looking at a combination strategy if you knew, for example, that TDXD monotherapy did so well in a second line setting. And truthfully, we didn't know that when we designed this study. So this study was designed because at the time we had some preclinical data suggesting that pertuzumab acted synergistically with TDXD. And so it made us wonder, could it enhance that efficacy we had seen with monotherapy in DBO 1. And so we took upfront patients with metastatic HER 2 positive breast cancer, cancer. They could either have de Novo or recurrent disease and they were randomized to get TDXD with or without pertuzumab or to get a taxane with trastuzumab and pertuzumab. The critical pieces of the design are that each of the TDXD arms were designed to be compared to THP. We were looking to see if TDXD and pertuzumab was better than THP or TDXD alone was better than THT THP. But the two TDXD arms were not designed to be compared to one another. And I think the other thing that's really critical with the design is that within the TDXD arms, patients were continued on TDXD until time of disease progression. Whereas within the THP arm, it was very similar to the way Cleopatra was given. Where THP was given with taxane, it was per investigator discretion, but usually patients were getting a median of 6 cycles of taxane and then stopping and going on to trustuzumab and protuzumab maintenance. But truthfully, physicians could choose to continue taxane for as long as they wanted within that arm as opposed to Cleopatra where you couldn't add endocrine therapy for ER positive patients. This trial did allow endocrine therapy to be added once taxane was discontinued or after at least six cycles of TDXT were administered. Some subtle differences in the design. What you saw was a very impressive improvement in progression free survival favoring TDXD and pertuzumab compared to THP. I would note that these data come from an interim analysis of the trial, not the primary PFS analysis. At this time. The P value to declare significance was extraordinarily stringent, so it was P less than .0043. To see that difference you had to have a very large difference. The monotherapy arm, the TDXD plus placebo arm did not meet those stringent criteria for success. Only the TDXC plus pertuzumab arm met those criteria. So patients in the TDXC plus placebo arm continue to remain on study and that arm remains blinded. We'll have to await the primary PFS data to see those results. But here you can see almost a doubling of PFS with TDXC and pertuzumab compared to THP. But ESMO. We saw some really nice subgroup analysis from the trial. A little over 50% of patients in DBO 9 had de Novo disease. You can see very impressive benefits within the de Novo patients as well as within the recurrent patients. The hazard ratios are fairly similar in that .5 to .6 range. The absolute PFS numbers are lower in recurrent patients compared to de Novo patients, but the relative benefits are similar. Comparing TDXD+Pertuzumab with Other HER2+ Regimens Well, thanks for that background, Sarah. These findings are undoubtedly amazing. And right from the inception of TDXD, we know that this is an active drug. This combination was just approved right after SABCS 2025. But at SABCS 2025, we also saw the data from her to climb O five study that is patients got THP and followed that was maintenance with Tecatinib which showed PFS improvement. Now if her to climb O 5 was to get approved in this particular setting, we'll have three options. That is traditional THP followed by HP maintenance, which is our approach based off Cleopatra regimen. Then Destiny brushed O9 with TDXD plus Pertussibab and also hard to climb O5 with Tucatnam maintenance. In your clinic. Sarah, can you share who would get TDXD plus Pertussibab and who might be a right candidate for Tucatnet based maintenance? Speaker 3 You bring up the key question that many of us, including myself are struggling with a bit at this time because these data from Destiny Breast 09, I think are very impressive, right? You're hitting over a 40 month median PFS at an interim analysis. So that may not actually be the true median. It could be much longer when you hit your primary PFS. Clearly, this is a great regimen, but the catch is you're leaving patients on continued chemotherapy until progression, which could be 3-4, five years, that's a long time. Whereas with the Cleopatra regimen you're giving an induction strategy with chemo for just 16 cycles and then patients are going on to maintenance. We've seen very impressive data from patina where you can add endocrine therapy and pelvic cyclone to your ear positive her 2 positive patients at time of discontinuation of taxane and get over 40 months of PFS. And with the her two Climo 5 regimen with adding to catnib to HP in the maintenance setting, we also saw significant improvements. While the absolute PFS numbers were lower than what we've seen either with DBO 9 or patina, that hazard ratio was actually very impressive. And so you are seeing significant risk reduction from adding to catnib to HP as well. And so it does beg the question, what do you start with? I'll be honest, it's hard to compare the studies to know what to do. And the reason is, is that with each of the her two Climo 5 studies in patina, patients had to not have disease progression on induction therapy to be eligible to go on to the maintenance strategy. And yet if you look at DBO 9 and the THP arm, you'll see at that six month mark, 12% of patients had actually progressed on THP. So those patients would not have been eligible to go on. And in DBO 9, half as many patients progressed through that initial 6 month period, meaning that TDXC is preventing some of those early progression events that wouldn't allow people to even get on to a palbo or to captain and maintenance. And so I think what we're all wondering is there a way where we could give people upfront TDXD, let people have a really robust response and then maybe switch them to a maintenance strategy? Obviously, this is not data-driven. We don't have any data to know what the efficacy would be if you used an induction maintenance type strategy, but switch the induction phase to be TDXD. We don't know how long that induction phase should be. Taxanes obviously limited by development of neurotoxins whereas TDXD is not. And so one could give TDXD longer really trying to hit someone into maybe a CR or PR and then switching them to maintenance. And so this is something that is being studied. For example, the Demeter study currently is enrolling that just gives 6 cycles of TDXD and a fixed number and then they go on to get HP. Right now, the trial does not allow adding on agents outside of endocrine therapy to the maintenance setting, although it will be amended to add pelviciciclib to the maintenance portion in the ER positive patients. So we won't have you know, it's a small study. It's like 160 a 170 patients. It's not randomized. It's not going to be definitive, but will give us at least a clue for how induction maintenance works. There are studies under development with Arizona and Dai Ichi to address this further because we need to understand duration. If I saw patients sitting before me today, what would I do? I think I would prefer giving them TDXD and pertuzumab upfront. Allow them to, to hit a really maximal response and then switch them over to HP, Maybe add endocrine therapy, Pebble if they're positive or to Catnib if they're, uh, negative. That would be my preference if I could get insurance to cover that. And that would probably be the ideal thing in my mind. So I think it's gonna be a patient by patient decision. Speaker 1 Sarah, thank you so much for touching all this. There's so much to unpack here. Just talking about this induction and then maintenance. We are in data free zone, but this is something we are questioning for every single her 2 positive metastatic breast cancer patient in front of us. Is there going to be a magical number in your mind for a trustezumab, dirkstecan and pertuzumab 6 cycles, 9 cycles or is it going to be more dependent on how they're responding and tolerating? Also before you switch any role of CTDNA here whatsoever? Speaker 3 A key question, we've been thinking about this a lot with the next trial that needs to be designed and how it should be designed, really hitting upon all your questions. We have looked into the data in Destiny Presto 9 trying to understand what is the time to hitting resist response with TDXT and pertuzumab. How does that differ in ER positive versus ER negative patients? When are patients hitting Nader for maximal response? So all of that is, are things we've tried to dig deep into to help us understand what that duration should be. Is going to be more than just six cycles of treatment. The problem is that I don't know what the magic number is, but I think it is longer. Could we personalize that more rather than just say X number of cycles? Should it be that we wait until someone hits, you know, a maximal response and then plateaus? Should it be until they become MRD negative, for example, and then switch them to maintenance? I think these are unknown questions truthfully and things that we all want to address with future trial designs. This is where the future's headed. There was some really cool data at San Antonio looking at MRD status in first line metastatic. Her 2 positive patients presented by my colleague Stefani Morganti looking at the exact sciences assay and the people who are MRD negative at one year were the people this was with Cleopatra had prolonged duration response. They were the people who had PFS over three years. It does make you wonder if you could use MRD to predict long duration response and figure out timing for maintenance. But again, we're in a data free zone and need in that area. Speaker 2 Right, Sarah, you just touched on this that we saw responsiveness with TDXT even in hormone receptor positive space. This is exactly where patina fits in. And at SABCS 2025, we did see updates from patina study that is maintenance palbociclip plus AI plus dual anti her two targeted therapy after initial THP. What we see is significant PFS now with Destiny breast O 9, TDXT, pertuzumab roll of tying that even with AI plus CD K46 inhibitor, How are you maneuvering through that? Optimizing Treatment for Triple Positive & CNS Metastatic Patients Yeah. If I were starting someone on TDXT and pertuzumab and they had hormone receptor positive disease, I would add on endocrine therapy to the TDXT and pertuzumab. At least you know in the trial after in DBO 9, it was after six cycles that we did that. In truth in the study very few patients did add endocrine therapy in the TDXT pertuzumab arm. We don't really know what the added benefit is, but I think it's not gonna hurt. So I probably would add it. I would not add pelvicycloid to TDXD and pertuzumab concurrently. That there is no safety data for doing that. Just so people are aware that if for example someone had to discontinue TDXD due to toxicity and you put them on HP and endocrine therapy, then you could add the pelvicycloid at that time. Speaker 1 Can I push you a little more here Sarah, based on her to climb of five, we can appreciate the importance of that endocrine therapy for those triple positive patients. So in that triple positive patient, should the right sequence be THP and then maintenance poblaciclib with aromatase inhibitor or going back to what we were just discussing, still sticking to something that's more active trust his Med Durk Stiken and perduzumab and then after initial response switching them to the maintenance of poblaciclib, aromatase inhibitor and pertuzumab. Speaker 3 Yeah. So question is, is the induction strategy better if you use TDXD plus P or taxane? I don't have a randomized trial to address that directly. But if you look at the DBO 9 curves, you will see that in the first six months, half as many people are progressing, making you think that the induction strategy with TDXDP is going to be superior to a taxane. How that bears out when people are using various maintenance strategies as though if people are adding to catnip or palbo to that, I don't know. But it does make you think there's gonna be less drop off within those first six months if you use TDXT. Speaker 2 And also with that nuance of CNS disease, if there is CNS disease present, does that change your treatment algorithm here at all? Speaker 3 Yeah, very important question. We do have such robust data with TDXD in the CNS where we've seen intracranial response rates of around 70%. I think very robust agent if someone has CNS disease and probably would be my preference for an agent to start over taxane based treatment. You know we also have TECAT nib though as a maintenance strategy which does have great CNS penetration. We saw the data from her two climb 05 in that study about 12% of patients had brain Mets that went into the trial. They had to be small asymptomatic brain Mets to go on to the study. When you look at those particular patients and you look at CNSPFS, we saw small trend. That number of events is very small, but a trend towards it being better in the TECAT nib arm and so it makes you think that it's a really reasonable strategy. We also saw data from Patina. Looking at the CNS data, there were only 4% of patients who had CNS disease at baseline and Patina, if you look at all the patients in the trial, rates of CNS progression were lower in the Pelvo arm relative to the non pelvic cyclobarm. A caveat with Patina is there was no mandatory CNS imaging that was done in that trial as opposed to her two climb 05. So I think you do have to interpret that data with caution. Palbo anticatinib could be helping prevent CNS disease, but personally I think the data with TDXD is just so robust in the brain in this setting. It would be my preference for a patient with brain meds. Proactive Management of TDXD-Related Toxicities and Monitoring I know a lot of our conversation here has been about that induction and then maintenance and that is because they're already touched on trusted Mavdur XD can at the end of the day, the new class antibody drug conjugate, it's chemotherapy, so we have to worry about side effects. We've briefly touched on the tolerability, but when it comes to TDXD, few things that are on our radar, fatigue, nausea, alopecia and of course, ILD. Sarah, can you touch on some common side effects and clinical pros, things like protuzumab bringing diarrhea on board? Speaker 3 With TDXD, we do know it is a highly a metagenic agent. So it is critical that we use three drug prophylaxis when giving TDXD treatment. So that I find works quite well in some patients. We sometimes add a fourth agent, sometimes I'll add olanzapine if people have delayed nausea with TDXD. The other issue is there is a risk of interstitial lung disease from using TDXD, with around 10% of patients developing ILD. We do need to monitor for ILD, so usually we're doing CT scans every six to nine weeks in these patients looking to see if they may have development of pneumonitis on imaging. If they have Grade 1 pneumonitis, you do need to hold treatment. I usually do administer steroids in those patients, though not required. I do think it helps with getting the ILD to resolve a little bit more quickly and then reimage usually in three to four weeks and restart. If the Grade 1 ILD is resolved to grade 0, meaning no longer present on imaging. You do have to dose reduce if it takes more than four weeks to resolve, but with grade 2 ILD, I do think it's really critical. If someone has symptomatic pneumonitis, you have to permanently discontinue TDXD. And that's pretty tough because patients are usually responding really well, but we just don't have safety data about continuing in that setting. So I think that's really important. You also bring up the fact that pertuzumab is being added to TDXD. Pertuzumab does have some GI toxicity with some increased diarrhea, so important to keep that in mind. It was interesting though at San Antonio we saw the patient reported outcome data from DB 09 which didn't show a significant difference in time to deterioration for pain or fatigue. It did show that TDXD was associated with more GI side effects relative to THP, for example, nausea, vomiting and Constipation though. I think that's probably because we give all those anti medic with the TDXD. So some some differences there. Speaker 2 And Sarah, you said that for Grade 2 and beyond, we should discontinue TDXD because the mortality is associated with ILD here with TDXD. With regards to the clinical trial, how it was conducted. And you mentioned that to do CT scans every 69 weeks, but out in clinical practice becomes rather difficult at times because of the insurance approval and everything. Is that what you do in your practice or you push it out to about 3 months, or rather get that six weeks to 9 weeks initially and then start pushing it out to three months? Speaker 3 You're right that we always have to go with what we can get covered. I tend to scan every six to nine weeks for the 1st 12 months. Usually I find 9 week scans are covered by insurance for the most part. Once you get to 12 weeks, we have seen that while ILD is still possible, it does plateau in terms of risk and so I feel more comfortable extending to every 12 weeks at that point. You know, all the Destiny trials did have scans every six weeks. We don't actually have data for what the optimal timing is of scans. Outside of a trial setting, but I tend to be quite conservative. As you point out, there is a mortality risk, so I like to just be careful monitoring, particularly that first year. Speaker 2 And how frequently are you monitoring echo with regards to dilated cardiomyopathy which is tied with the her two targeted agents? Speaker 3 With all her two targeted agents, we do have some risk of congestive heart failure. I tend to do it a little less often in the metastatic setting. Our, our group tends to get an echo at baseline and then we tend to just do every six month echoes in the metastatic setting. You know, obviously in the early stage setting I'm doing every three months, but in the metastatic setting our thresholds are a little different to discontinue our hold. I tend to be a little more liberal here. Speaker 1 You know, there was data from your group as well a poster presentation particularly with these antibody drug conjugates from metastatic settings. We truly don't have guidelines on how frequent we should get echo and data is actually suggesting that cardiomyopathy might not be as high as we initially thought with these newer ADC's. OK, Sarah, before we close, any final thoughts here on this recent approval? Dr. Tolaney's Final Thoughts on HER2+ Breast Cancer Advances Oh, I think I'm just really excited to see TDXDM pertuzumab approved for metastatic HER 2 positive disease. This benefit in terms of progression free survival is really quite striking. So really important for our patients to have access to the drug from the get go once they have metastatic disease. Speaker 1 Sarah, thank you again for your time, for your expertise, and importantly for getting these treatment options available for our patients. For our listeners, let's go over a quick recap from today's discussion. Speaker 2 In today's discussion, we're Doctor Sarah Tulaney, the lead author of Destiny Breast 09. We touched on the recent FDA approval of TDXD plus pertuzumab at the first line treatment option for metastatic HER 2 positive breast cancer. In this study, we saw significant PFS improvement of 40.7 months compared to 26.9 months. Here the hazard ratio was 0.56. Speaker 1 We also had a chance to put this all in clinical context as we also saw recent data from her to CLIMO 5 with two catnip based maintenance option with TDXD and protuzumab from Destiny Breast O 9. We do have to keep an eye out for fatigue, nausea, alopecia, and ILD. How in clinical practice will likely sway away from all our patients. Being on TDXD and pertuzumab forever will likely rely on maintenance therapy after seeing that good initial response or if you run into issues with tolerability. Speaker 2 Raul, I agree we have to keep all this in mind, but given the profound benefit here, this is in fact our new standard of care. Thanks for joining us. Tune back in for more treatment algorithms, FDA approvals and conference highlights. We are the oncology brothers.