Chapters Transcript Video Case #4: Neo-adjuvant Therapy in HER2+ Breast Cancer Back to Symposium This is Doctor Haley Newman, also from the University of Pennsylvania. Thanks. All right. I think I'm the last one. so, and the theme of my presentation today is TDXD, um, which is really exciting data coming out of ESMO in San Antonio this year. Um, so, sorry, I gotta move this up, guys. A Little taller than everyone else. All right. I can do um. All right. Um, so I'll be talking about DB 11, um, in the neoadjuvant space, DBO5, which is moving TDXD into the adjuvant space, and then a short slide or two about, um, adjuvant endocrine therapy choice. So this is all curable, HER2 positive breast cancer. So, DB 11, um, you know, this was, uh, presented at ESMO, definite unmet need in these patients, um, where we've had no new, um, therapies in over a decade, um, for early-stage HER2 positive breast cancer. We've long known that pathologic complete response is a surrogate marker for cure. I remind patients of this so often when talking about neoadjuvant therapy and prognosticating for patients in their survivorship era. Um, and, um, you know, ultimately, if we can achieve a path CR for more of our patients, we can save them the burden of the toxicity with, with more aggressive adjuvant therapy. So, very important to find more, um, effective and tolerable neoadjuvant therapy, uh, for HER2 positive patients. And we know that TDXD has now shown significant, uh, benefit in the metastatic setting. So it's moving up the ranks, um, which is really exciting. So here comes DB 11. Um, so looking at the study design, these were patients with previously untreated HER2 positive early breast cancer. And just to point out, these were really high-risk patients. These patients had either T3 disease, um, who with any nodal status or, um, nodal involvement. So these are not the, you know, the most common like T2N0 HER2 positive patients. That we see really frequently. These are either T3 and above or node positive disease. Um, inflammatory breast cancer patients were also included, which is sort of rare, um, in these studies. So that's also nice to see. And this study had a three-prong design. Um, the TDXD only arm was actually ended early because that showed a lower than expected rate of pathologic complete response. So, what we focus on here is the top two. In blue, TDXD for 4 cycles followed by THP and the standard of care arm, um, which ACTHP arguably something that many of us don't use anymore, but still something that is used worldwide. Um, so again, swapping TDXD, an antibody drug conjugate for the 4 cycles of AC and comparing these 21 to 1. Again, just to highlight, uh, in the demographics, these patients were, um, were very high risk. The vast majority of them, um, almost 90% of these patients were node positive. Oh, and I think one other thing, oh, the majority were also hormone receptor positive. So this to me makes the numbers even a little more impressive when knowing that patients with hormone receptor-positive disease are generally associated with lower rates of pathologic complete response. So again, a high, um, hormone receptor-positive patient population and a high lymph node involved population. Uh, primary endpoints, um, looking at pathologic complete response is pretty impressive. Um, so in the intention to treat population, um, in the TDXD followed by THP arm, pathologic complete response rate of 67%, which is pretty great, and, uh, compared to 56% in the standard of care ACTHP arm. Over on the right side of the screen, they broke down hormone receptor positive and hormone receptor negative. Um, as expected, the hormone receptor-positive patients did a little bit worse, but still had a, um, improvement, um, over, uh, the standard of care with the TDXD. And look at that path CR in the ERPR negative patients who received TDXD 83%, uh, rate of pathologic complete response. This is pretty remarkable. Um, Secondary endpoint event-free survival was also improved, um, at 2 years, about 97% versus 93%. So this is early, um, but a positive trend was observed favoring the TDXD. Um, a couple of AEs of special interest, of course, um, interstitial lung disease. Um, interestingly, um, the interstitial lung disease was actually, um, equivalent between these two arms, which was a surprise to me. You'd certainly think. Um, you know, that with giving both, uh, TDXD as well as ataxane, both of which can cause pneumonitis, that you would see higher rates of ILD, but that was not observed in the study. And then not surprisingly, higher rates of cardiac dysfunction in the standard of care, ACTHP group. Um, but again, arguably, that's not the regular standard of care that most of us use today. Instead, we use a non-anthracyclin TCHP. So that's been one, Uh, negative thing about this study. A little blurry, but generally, toxicities with, um, the TDXD, so looking at the dark blue and the gray, TDXD had higher rates of nausea, which was also maybe a little surprising when you're comparing it to an anthracyclin. Um, higher rates of neutropenia in the standard of care arm, um, and a little higher rates of neuropathy in the TDXD arm, which maybe also surprised me a little bit. Um, the discussant in the study pointed out that there was actually less antiemetic use in the TDXD arm. Perhaps because we think about AC as a just a highly emettogenic regimen, and patients were more heavily or more aggressively pre-treated with anti-emetics on the AC arm as opposed to the TDXD arm. So the, um, the discussant pointed out that anti-emetics, um, should certainly be more aggressively, um, you know, it's a way to improve toxicity to, uh, improve our antiemetic regimen for our patients. So, conclusions here were that TDXD times 4 cycles followed by THP x 4 cycles in the neoadjuvant setting has now shown the highest reported path CR rate for HER2 positive patients in the early breast cancer setting. Um, the, um, you know, these results ultimately support TDXD as a more effective and generally less toxic option. Um, and may become a preferred regimen for our patients with HER2 positive disease. Um, so, I think that we skipped over the initial case, but ultimately, um, we have a, um, um, oh, I guess we're switching now to DBO 5. so, I think ultimately, my take-home points from the DB 11 study are that I, I think this is really exciting. Um, that, you know, this is not an approved approach yet, but this is something that I've personally done, antibody drug conjugate followed by a taxing regimen in our ISpy study at Penn. And I think that in general, our patients have really tolerated this very well, um, and I've seen really great responses on our ISpyY study. Um, I think that They're, you know, keeping in mind that this was not for everybody. These were very high-risk patients, T3 or node positive patients, um, but generally a tolerable and very effective regimen. I do fear if using this regimen, what are we going to do for the patients who have residual disease after TDXD? Perhaps that's not the reason not to use it, but the, that is a really high, you know, unmet need in our clinic. Wherever you're using TDXD when patients progress or don't respond well to that, we are in just such a, such a difficult situation. So, um, One thing to kind of think about here. Do we want to use 4 cycles of TDXD in the neoadjuvant setting, or do we want to save our blockbuster drug for the adjuvant setting? Um, so this brings us into DBO5. So, we have a patient who has T2N1 triple positive breast cancer. She received neoadjuvant TCHP. Her response was modest. Um, she had a mastectomy with sentinel lymph node biopsy. She had multifocal residual disease, um, with 3 or 4 lymph nodes involved, lymph node dissection with a few more lymph nodes involved. At that time, she had a staging study, um, showing no evidence of distant metastatic disease. So, other than radiation, what are we going to offer this patient? So, DBO5, um, is moving, is comparing, uh, TDM1, which is our current standard of care, to TDXD in the adjuvant setting for patients with residual disease after neoadjuvant chemotherapy. And again, a very high unmet need. Um, the Katherine study, which was published now, almost a decade ago, um, has been our standard of care in this very high-risk setting, and we, we need to do better. Um, we worry about patients who recur, um, you know, in these sort of treatment resistant patients with brain mets, distant recurrences remain of high concern in everyday clinic, um, In our breast clinic. So, this was an open label phase 3, worldwide study, uh, comparing TDXD and TDM1. So, again, sort of similar to DB 11, these were very high-risk patients. Um, these were patients who either at presentation were considered to be inoperable or operable disease with nodal involvement after neoadjuvant chemotherapy. So again, this is not your patient who cleared their nodes with maybe a little spot or multifocal disease in the breast. These are patients with nodal involvement after neoadjuvant chemotherapy. And or patients who had inoperable disease at baseline, which inoperable disease really isn't all that common. But again, this is very high risk population. Uh, this study randomized patients 1 to 1 to TDXD versus TDM one. Um, again, um, again, a high population of hormone receptor positive patients. And again, just highlighting, again, how, um, high risk these patients were, with about half of the patients being considered inoperable prior to neoadjuvant chemotherapy. So again, not the most common patient we encounter in our clinic. Um, impressive invasive disease-free survival, which was the primary endpoint of DBO5. There was a, um, 8.7% difference in invasive disease-free survival at 3 years. Um, so, pretty impressive, uh, associated with a 53% reduction in the risk of invasive disease or death with, uh, given TDXD over TDM1. So, really impressive, nice P value there. Um, An important point, um, with DBO5 is that TDXD also showed reduced CNS recurrence, which is just oh so important in these very high-risk patients. Um, in the navy blue line or the, in the graph, the second area, um, where they're showing distant recurrence, the CNS recurrences were numerically reduced, um, in the TDXD group. Uh, and distant recurrence significantly reduced. So again, um, these, I mean, I really, you know, this is very reassuring that we are actually helping prevent distant, uh, relapses by giving this, um, TDXD over TDM one. So what about radiation therapy and TDXD? Because, um, you know, generally, I don't know how, how y'all do it, but I generally, uh, recommend giving radiation, uh, in, uh, concurrently with TDM one, mostly just to kind of get people going with their treatment. And there's certainly a concern about pneumonitis, um, when you're giving radiation and TDXD concurrently. So, all patients on this study got chest CTs every 6 weeks, which I think is definitely not something that I've ever really done in practice. I think my own practice has waxed and waned over the years, um, with chest screening, but just keeping in mind that these studies or these patients were monitored so closely for ILD. Um, in the study, radiation was allowed to be given concurrently or sequentially. Um, and in total, nearly 10% of patients who received TDXD developed pneumonitis, um, during the course of the 14 doses of the drugs as opposed to about 1.5% of those receiving TDM1. Interestingly, the radiation did not seem to impact the development of drug-related ILD. Um, and the last line also piqued my interest where it says the rates of radiation pneumonitis were similar, and they were between the two arms, where around 30%. Um, this is definitely way higher than we would see in a typical practice, but I, these were mostly grade one events, which means they were asymptomatic. So, basically, this Q6 week CAT scan was just picking up a lot of people who had radiation pneumonitis that was asymptomatic. So, to me, that is sort of an, maybe a clinically, maybe sort of insignificant number. I'm more so I'm looking at the 10% versus about the 1.5% of the drug-related ILD which is the more diffuse, um, Uh, pneumonitis. So, the discussant said these studies further characterize benefit and safety profile of TDXD over TDM one in the post neoadjuvant HER2 positive early breast cancer space. Very exciting. Um, again, safety summary, I think I'd kind of already talked about some of that. Um, so conclusions from DVO5 were that the IDFS improvement was consistent across different subgroups. Um, the timing of radiation, whether given concurrently or sequentially, did not, thankfully, did not seem to impact the development of pneumonitis. Um, the drug-related ILD were generally, um, manageable, and, um, these patients were treated with steroids. Um, while differences, um, uh, actually, I'll skip that part. Um, so overall, the authors concluded that there was a, that this was tolerable and considered generally pretty safe and continues to support TDXD as a potential new standard of care. Um, so what was the impact of this study? Well, the New England Journal, um, published DBO 5 December 10th, so hot off the presses. And as of three weeks ago, TDXD was granted breakthrough therapy designation for post neoadjuvant therapy for patients with HER2 positive early breast cancer. So, um, I think that this, as opposed to the neoadjuvant data, I think this is something that I'm, I'm really ready to apply to my own clinic, perhaps not for everybody, but maybe for those really high-risk patients. So back to our case. Um, patient who had neoadjuvant, uh, neoadjuvant TCHP with residual disease, multiple lymph nodes involved after neoadjuvant therapy, very, very high-risk situation. She received adjuvant radiation. We decided to treat her with adjuvant TDXD for 14 cycles, which she tolerated pretty well. So, now, what about her adjuvant endocrine therapy? This is maybe the lesser exciting part, but still important. This was a, um, study looking at, um, uh, called the ALTO trial, which now has, uh, 10 years of follow-up. This was a large study looking at early breast cancer in the curative intent setting for HER2 positive disease. In this study, they took the 2500 or so patients with hormone receptor-positive disease and looked at what was their best endocrine therapy, tamoxifen versus an aromatase inhibitor. And the authors pointed out that this was something that made this, um, sort of an important study is that it was the largest adjuvant study in the HER2 positive space, and also a modern study, because a lot of these endocrine therapy studies are including patients that did not even receive Herceptin because they were such old studies. So this was sort of a modern day, uh, endocrine therapy study. And what we learned, maybe not surprisingly, is that disease-free survival was better in those receiving aromatase inhibitors, um, about a 3% difference at 10 years. So that seems real. Um, there was less rates of local recurrence, less rates of distant recurrence. So, I think I'll buy it. I think AIs are generally what most of us are doing, um, for our patients who are especially high risk, but this is, you know, just, um, uh, supporting, I think the practice that a lot of us already have. Um, they looked at subgroup analysis of pre-versus postmenopausal patients, and the disease-free survival was, uh, the same. Um, the patients, uh, did very well, although there were fewer patients who received aromatase inhibitors, so a pretty small group, but basically still a disease-free survival benefit regardless of pre versus postmenopausal women with aromatase inhibitors over tamoxifen. So, um, this study, you know, big study looking at the appropriate endocrine therapy, and for our patient, we're going to give her an AI after she's had her preoperative chemotherapy, surgery, radiation, TDXD. We're going to add on an AI for 5 to 10 years, and she's going to do great. Um, so, what about for our APPs, um, and just kind of day to day life in clinic? Um, I put in a couple of, of graphs regarding, um, ILD management in, in patients receiving TDXD because I think this is really going to be the biggest toxicity thing that we have to manage, um, when we're making the switch from TDM one to TDXD. I think we need to be very cautious about nausea and make sure that we're aggressively managing our patients with a good antiemetic regimen. And we need to be very thoughtful about screening patients. If you're not going to be getting frequent CTs like I generally don't, um, asking patients every visit if they're having any symptoms, cough, shortness of breath. I, I do that every visit in a patient on an HER2, whether they've TDXD, whether they've been on it for one dose or 30. Um, so it's a little blurry, but anyways, um, I think those are the big things. So, in conclusion, my dogs, bacon and ham are going to wave us all goodnight. Um, Uh, neoadjuvant TDXD followed by THP I think is a very exciting option. Not sure if we're totally ready for prime time yet. My interest has piqued, and I would certainly consider thinking about it in a patient with very high risk disease that, um, that matched the trial. So the patients who were, you know, the really high risk, node positive, big tumors, um, adjuvant TDXD, I think I'm in. Um, I'm definitely. Ready to use this. I haven't used it yet. Um, but the 8.7%, uh, invasive disease-free survival at 3 years, I think is very impressive. The, uh, tolerability, you know, the 10% risk of ILD was, um, you know, pretty much what we've seen with using this many doses of in, uh, of TDXD and other studies. So, I think that this is a really viable treatment option, particularly for our most high-risk patients. I continue to have concern about what we use when someone recurs after getting TDXD in the neoadjuvant or in the adjuvant setting. So I think that's all a story still to be determined. But, um, I think that I've, you know, probably had with these two studies, two of the most exciting, um, studies that came out of ESMO and then with these interim analysis discussed at San Antonio. And I think that's it. I'm not as tall as Doctor Nollman. Thank you all for attending our meeting today and a special thank you to all of our presenters and exhibitors. A big round of applause for everyone. Created by Related Presenters Hayley Knollman, MD Assistant Professor of Clinical Medicine(Hematology-Oncology)Penn Medicine
