Listen to breast cancer experts discussing clinical highlights from a recent webinar on new data and clinical updates presented at the 2025 San Antonio Breast Cancer Symposium, including answers to outstanding questions in the field of breast cancer care.
Listen to learn from Sara M. Tolaney, MD, MPH, and Virginia Kaklamani, MD, DSc,
about new clinical trial data and updates informing the care of patients with early breast cancer and locally advanced/metastatic breast cancer that were presented at the 2025 San Antonio Breast Cancer Symposium.
Presenters:
Sara M. Tolaney, MD, MPH
Chief, Division of Breast Oncology
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Virginia Kaklamani, MD, DSc
Ruth McLean Bowman Bowers Chair in Breast Cancer Research and Treatment
A.B. Alexander Distinguished Chair in Oncology
Leader, Breast Oncology Program
UT Health San Antonio
MD Anderson Cancer Center
San Antonio, Texas
Link to full program:
https://bit.ly/46Qv9OK
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr Sara Tolaney (Dana-Farber Cancer Institute): We were really excited to see data in the metastatic HER2-positive setting in the HER2CLIMB-05 study.
This study looked at adding tucatinib to trastuzumab and pertuzumab in the first-line maintenance setting. Patients got upfront taxane with trastuzumab and pertuzumab for 4 to 8 cycles. If they had disease that was either stable or responding, they could then enroll into this study and get randomized to HP maintenance or HP plus tucatinib, with the primary endpoint being progression-free survival.
About 12% had brain metastases at baseline. So patients were allowed to have small asymptomatic brain mets that could be either treated or untreated at time of enrollment.
This is a bit higher rate of brain metastases in the first-line setting compared to what we saw in DB-09, where it was about 6% and about 4% in PATINA. That probably reflects some bias in terms of preference to enroll a patient onto a study that has a CNS penetrating TKI.
the prevalence of de novo disease was 70%. This is a lot higher than we have seen in other first-line trials. Most of the other first-line trials had about a 50% enrollment of de novo patients, as we had seen in DB09 and PATINA.
HER2CLIMB-05: Investigator-Assessed PFS (Primary Endpoint)
It was very impressive to see that there was about an 8.5-month absolute improvement in progression-free survival, favoring the addition of tucatinib to HP therapy, taking PFS from around 16 to almost 25 months with a hazard ratio of 0.64.
I will say, however, the absolute PFS numbers that we are seeing here were a lot lower than many of us anticipated. It is important to note that only 45% of those patients in the ER-positive subset did receive endocrine therapy you are allowed per physician discretion to add endocrine treatment, but it was a little less than half the patients that did so that certainly could have brought down the absolute PFS for the HR-positive subset in both arms.
HER2CLIMB-05: PFS by Subgroup
The relative benefit across various subgroups was very consistent across all of these subgroups.
HER2CLIMB-05: PFS by BICR and Hormone Receptor Status
What I think was important to note is that the hazard ratio for benefit was larger in the hormone receptor-negative patients compared to the hormone receptor-positive patients.
In the HR-negative subset, the hazard ratio is about 0.55. the HR-positive subset, hazard ratio of about 0.73. What is interesting though is if you look at the absolute PFS for the tucatinib arms, it is almost identical for the hormone receptor-positive and negative patients. It is that the control arm is actually performing quite differently for the hormone receptor-positive vs negative patients.
HER2CLIMB-05: OS and CNS-PFS
Of interest certainly was what is going on with the brain, because here we know that this is a HER2 TKI, has known survival benefit in patients with brain mets. This is however the first-line setting. I would caution you that CNS events are lower in this upfront setting.
I think we are going to need longer follow up to see these differences, because right now the number of events separating the 2 arms in terms of CNS events is quite small.
OS data is highly immature at this time point, but a very nice trend favoring the addition of tucatinib.
I took away from this trial that adding tucatinib to HP maintenance should be practice changing. It is clearly improving PFS across these patients.
HER2CLIMB-05: Safety Summary
It is also important to factor in toxicity, because we do know that diarrhea and hepatic toxicity are common side effects with tucatinib. In fact, there were more discontinuations and more high-grade events and serious adverse events in the tucatinib arm compared to the control arm. Most of the discontinuations were due to elevated liver enzymes, as well as some due to diarrhea.
HER2CLIMB-05: Treatment-Emergent Adverse Events
Overall rate of diarrhea, it was about 70% in the tucatinib arm with about 6% grade 3 events. Looking at the LFTs, about 25% of patients do get elevated LFTs.
Onset for hepatic toxicity, is about 40 days and for diarrhea about 50 days.
PATINA CNS Outcomes: Palbociclib + Anti-HER2 + ET in Previously Treated HR+/HER2+ MBC
Putting this into context is important because we have previously seen data from the PATINA study, which had looked at adding palbociclib as maintenance to HP endocrine therapy in that first-line, ER-positive, HER2-positive setting, where we had seen a significant 15-month absolute improvement in PFS from the addition of palbociclib and we are all highly anticipating a potential approval for palbociclib in this upfront maintenance setting.
One question that we have all wondered about was, does palbociclib have an impact on rates of CNS events, particularly relevant given what we just saw with tucatinib?
The investigators from the PATINA trial did look at this. I would, however, caution, as we do look through this data, that there was no mandatory CNS imaging in this trial. No mandatory CNS imaging at baseline, no mandatory CNS imaging in the follow up setting, or at time of progression for those patients who did not have CNS metastases at baseline. This is different than HER2CLIMB-05, where mandatory CNS imaging was required. Even in those patients without baseline brain mets, they were required to get it at baseline in every 6 months and at time of progression.
You have to interpret the PATINA data as more real-world data with not the same level of evidence as the HER2CLIMB-05 data would have for CNS events, but really important data to see.
PATINA CNS Outcomes: Cumulative Incidence of CNS Progression or Death (All Patients)
The cumulative incidence of CNS progression, looking at the palbociclib arm, you could see there were fewer CNS events within the palbociclib arm compared to the control arm, so 14% compared to about 20%. This is fairly consistent in terms of benefit favoring the palbociclib arm compared to the control arm over time.
This was also true for the patients who did not have brain metastases at baseline. I would note, that only about 4% of patients had brain mets at baseline in the PATINA trial. Again, they were not screened with mandatory CNS imaging.
Here there is certainly a trend potentially favoring that palbociclib could be impacting that.
DESTINY-Breast09: PROs With T-DXd + Pertuzumab vs THP as 1L Therapy in HER2+ Advanced or Metastatic Breast Cancer
Obviously, another potential choice for treatment in the first-line setting is now T-DXd plus pertuzumab. This combination recently FDA-approved based on the DESTINY-Breast09 trial. This trial had taken patients in the upfront metastatic HER2-positive setting and randomized them to get T-DXd with or without pertuzumab and compared it to the CLEOPATRA regimen, THP.
The study had demonstrated that at an interim analysis, the T-DXd pertuzumab arm had led to a significant improvement in progression-free survival compared to THP, with a PFS of a little over 40 months compared to 26 months, again, leading to its recent approval. The T-DXd monotherapy arm still remains blinded, and those patients remain in follow up.
While we do have this regimen approved, certainly one question is, what is the impact on quality of life? One would imagine that getting upfront induction treatment with THP followed by HP maintenance may be better tolerated because patients are not continuing to get cytotoxic therapy until time of progression. These data were important because it did look at PROs.
DESTINY-Breast09: Overall Treatment Tolerability
What was interesting to me when looking at these data is when patients were asked how bothered they were by side effects from treatment in each arm, the similar percentage of patients reported being not bothered at all or a little bit within T-DXd plus pertuzumab arm compared to the THP arm. There was similar reports of tolerability with the patient global impression of treatment tolerability scale.
DESTINY-Breast09: PRO (Secondary Endpoint)
We also saw there were no differences in risk of clinical meaningful deterioration in pain between 2 arms. There was however more impact of T-DXd pertuzumab on GI toxicities where we did see more appetite loss, constipation and nausea and vomiting with T-DXd and pertuzumab compared to the control arm.
ASCENT-07: Sacituzumab Govitecan vs CT as First Post–Endocrine Therapy in HR+/HER2− MBC
I think seeing DB-09, PATINA and HER2CLIMB-05 data all at San Antonio does lead to a really robust question about what should we be doing in the upfront setting for our patients.
Another trial that was highly anticipated at San Antonio was the ASCENT-07 study. This trial was trying to move sacituzumab up earlier for metastatic hormone receptor-positive breast cancer. We obviously have sacituzumab approved based on the TROPiCS-02 study, which had demonstrated an improvement in PFS and OS in a pretreated population. This study was looking to see how sacituzumab compared to chemotherapy in patients who had only progressed on endocrine treatment, not any prior chemotherapy.
Patients were randomized to sacituzumab or treatment of physician's choice chemo, with the choices being capecitabine, paclitaxel or nab-paclitaxel.
The primary endpoint was progression-free survival by Blinded Independent Central Review.
ASCENT-07: Previous Therapies
The majority of patients had had prior endocrine therapy with CDK4/6 inhibition, about 90% of patients, which, would be consistent with our current practice patterns.
ASCENT-07: PFS by BICR (Primary Endpoint)
We were a little bit surprised with this finding, though, is that there was absolutely no difference in progression-free survival between sacituzumab and standard chemotherapy in these patients who are chemotherapy naive for metastatic disease. The Blinded Independent Central Review PFS was a little over 8 months but identical between the 2 arms at 8.3 months.
It is really important to realize, that there were patients who were randomized to the control arm who did get censored, so they pulled out of the trial prior to BICR-confirmed PFS and more of them went on to get a subsequent ADC.
In talking to the investigators, they did feel that the investigator-assessed PFS that was occurring at these time points was really due to seeing a new lesions that were seen, just not meeting BICR-confirmed events.
ASCENT-07: Subsequent Anticancer Therapy
Here again, you are seeing higher use of subsequent ADC in the control arm at about 60% compared to 30%, reflecting, what many of us would anticipate in this study where it is not blinded to drug.
ASCENT-07: Tumor Responses and DoR by BICR
Objective response rates are fairly similar between the 2 arms. Duration of response is actually longer with the sacituzumab arm compared to chemo. Again, really intriguing because we continue to see the signal with sacituzumab that duration of response seems to be much longer with this agent, making me wonder if there is an immune-based mechanism to the ADC leading to this.
ASCENT-07: Treatment Exposure and Safety Summary
When you look at treatment discontinuation, it is fairly similar between the 2 arms. There were more grade 3 adverse events with sacituzumab compared to chemo.
ASCENT-07: Most Common TEAEs (in ≥20% of Patients)
Toxicity profiles in line with what we already know with sacituzumab. Certainly, high rates of neutropenia, more grade 3/4 neutropenia, more in the way of diarrhea compared to chemotherapy, but less in the way of things like neurotoxicity.
ASCENT-03 Safety Analysis: Sacituzumab Govitecan vs CT in Previously Untreated Advanced TNBC Ineligible for PD-(L)1 Inhibitors
There was a difference for PFS based on investigator-assessed PFS.
Again, this study does not conclude that sacituzumab is better than chemotherapy, and so will not change practice patterns, but will lead to sacituzumab being used in a pretreated population for metastatic hormone receptor-positive disease.
If we switch gears and think about the triple negative setting and data we have seen with TROP2-directed ADCs, this has been an exciting area given that we have seen a recent data, both from ASCENT-03, 04 and TROPION-Breast02 in this first-line metastatic triple-negative setting.
We have seen the efficacy data previously presented. At San Antonio, we saw the safety analyses.
Again, ASCENT-03 compared sacituzumab to chemotherapy in the first-line setting for patients who are deemed to be ineligible to immunotherapy, so patients who were PD-L1 negative, or have a comorbidity for which they could not get an immunotherapy agent. They got assessed for PFS as a primary endpoint. We have previously seen that sacituzumab did lead to a significant improvement in PFS with a hazard ratio of about 0.6, and have now seen these data actually published in The New England Journal (of Medicine).
There were more deaths in the sacituzumab arm. There were 7 deaths that had occurred in this arm. Six were considered treatment-related and did result from infection. When you look at this data more carefully, you do see that 5 of the patients who died of infectious-related complications did so without receiving any growth factor. And yet all of these patients with the current guidelines would have met criteria for administration of growth factor treatment.
Just a very important reminder that when you are treating patients with sacituzumab, do consider growth factor utilization in patients who do have prior issues with neutropenia or have comorbidities or older patients.
ASCENT-03 Safety Analyses: Exposure-Adjusted Incidence Rates
When you look at the exposure-adjusted analyses, you do see that there are fewer issues with thrombocytopenia, anemia, and neuropathy with sacituzumab compared to chemotherapy. But you do see more diarrhea related to sacituzumab compared to standard chemotherapy.
ASCENT-03 Safety Analyses: Time to Onset, Duration of Neutropenia and Diarrhea
When you look at the time to onset of neutropenia, it is not that different between the 2 arms, but you do see earlier onset of diarrhea with sacituzumab compared to chemotherapy.
ASCENT-03 Safety Analyses: Management of Neutropenia
The use of primary prophylaxis did result in a significant decrease in rates of neutropenia.
ASCENT-04 was the study we had previously seen reported at ASCO that had demonstrated that the combination of sacituzumab and pembrolizumab resulted in a significant improvement in PFS compared to standard chemo pembrolizumab for first-line PD-L1 positive patients.
When we look at the toxicity from this trial, we can see with an exposure-adjusted incidence rate that actually there was less in the way of need for dose reduction or discontinuation of therapy with sacituzumab compared to the chemo-pembrolizumab arm, there was less in the way of anemia, thrombocytopenia and neuropathy with the sacituzumab, but more in the way of diarrhea and colitis with the sacituzumab.
ASCENT-04 Safety Analyses: TEAEs of Special Interest With Pembrolizumab
One really intriguing finding was there was also less in the way of immune-related toxicities with the combination of sacituzumab and pembrolizumab. This is particularly reassuring because we do worry about diarrhea as a common side effect with sacituzumab. And you would worry about issues with IO colitis, potentially with sacituzumab pembrolizumab. But that rate was not higher with the use of the combination compared to chemo IO.
ASCENT-04 Safety Analyses: Neutropenia and Diarrhea
Again, with the neutropenia and diarrhea, 2 common side effects with the sacituzumab, at median time to onset, it is shorter for diarrhea with sacituzumab-pembrolizumab compared to chemo-pembrolizumab. But time to onset of neutropenia is fairly comparable between the 2 arms.
TROPION-Breast02: Safety of Dato-DXd vs CT in Previously Untreated Patients With Adv TNBC Not Suitable for IO
When we look at TROPION-Breast02, this was a trial that looked at datopotamab deruxtecan or Dato-DXd compared to chemo of physician's choice in the first-line IO ineligible population. We saw these data presented at ESMO that did demonstrate that Dato-DXd led to an improvement, not just in PFS but also response rate and overall survival when compared to chemotherapy.
At San Antonio, we saw data that specifically focused on the safety analysis.
TROPION-Breast02 Safety Analyses: Treatment-Related AEs
When we look at any grade toxicities, they are fairly similar between the 2 arms as well as grade 3 and higher toxicities, as well as serious adverse events. Suggesting that this is fairly similar between the 2 arms. There were fewer treatment-related discontinuations, within the Dato-DXd arm compared to the chemotherapy arm.
TROPION-Breast02 Safety Analyses: AEs of Special Interest
Two important side effects to keep in mind with Dato-DXd are mucositis as well as ocular surface toxicities. We did see mucositis occur in about 60% of patients. This was despite the recommended use of decadron swish and spit for prophylaxis, with about 8% experiencing grade 3 mucositis. For ocular surface toxicity, it was about 50% of patients that had ocular surface events, with the majority of these events being dry eyes.
They did specifically also look at time to resolution and time to onset of these toxicities. Time to onset being about 26 days for stomatitis and about 77 days for ocular surface toxicity.
Now we are going to turn to the early stage setting.
monarchE, as we all know, is the adjuvant trial looking at abemaciclib in patients that had a high-risk of recurrence. This is an update looking at nodal status here.
Now, all patients on monarchE had at least 1 positive lymph node, but there are different categories of risk.
As a reminder, early-stage HR-positive/HER2-negative breast cancer patients randomized to either standard of care endocrine therapy or standard of care endocrine therapy plus 2 years of abemaciclib.
Now we had an update at ESMO with these results showing an improvement in overall survival, really a big deal in the adjuvant setting.
monarchE Nodal Status: Baseline Characteristics
Let us look at the nodal status because there is always a question, especially as we are adding therapies and we are increasing the toxicity profile for our patients. Is it really worth giving these treatments even in our lower risk patient population?
Here they broke it down into node 1, N1, N2 and N3 disease. Again, the N1 had to have high-risk features. So it was not all N1 disease patients.
As looking at both iDFS and distant relapse-free survival, you can see that there is a benefit that is persisting regardless of the burden of nodal disease.
Now, in looking at the absolute benefit, the more disease burden you have, the higher the absolute benefit there is from the addition of abemaciclib. Even in that N1 high-risk patient population, there is a benefit with the addition of abemaciclib.
NATALEE: Distant DFS Across Key Subgroups with Ribociclib + NSAI in HR+/HER2− EBC (a 5-Yr Report)
Now NATALEE is a similar trial, but with ribociclib instead of abemaciclib. Ribociclib was given at a lower dose compared to what we give in the metastatic setting, so 400 milligrams. It was given for 3 years.
Now, the other difference which may be important is that when we give ribociclib to patients, we cannot give it in combination with tamoxifen because of the QTc prolongation. In this study, the AI partner to ribociclib was a nonsteroidal aromatase inhibitor.
This study included lower risk patients that compared to monarchE. It included some node-negative patients, and all node-positive patients were included in the trial. We also saw an update of this trial at ESMO, showing again a continued benefit with ribociclib. Here they looked at several subgroups of patients.
Part of what we were also looking at, which we have seen before, is this node-negative patient population that has a higher risk of recurrence, should we be giving ribociclib to these patients?
NATALEE: DDFS and DRFS in ITT Population
DDFS, DRFS was consistent with the benefit of ribociclib that we have seen in the past. The longer the follow up, the longer these curves are separating, again, showing us a benefit with giving ribociclib for 3 years.
Then when looking at the different stages of disease, there is consistency. Even in the lower stage patients, lower risk patients, stage IIA, there still is a benefit from ribociclib. As we are increasing the stage IIIA, stage IIIB, IIIC, we are seeing at least the absolute benefit increasing. But there is a benefit in that lower risk patient population suggesting that patients that meet the criteria for NATALEE, we should consider giving ribociclib to these patients.
NATALEE: Site of Distant Recurrences
Something interesting that we have not had a lot of data on. So far, we have had a small series from Dana-Farber looking at this. But who are the patients that develop metastatic disease that have been exposed to a prior adjuvant CDK4/6 inhibitor? And what are the characteristics of these patients? The patients that had distant metastatic disease, most of them developed metastatic disease to the bones, although liver was next. There is a numerical difference between the ribociclib arm and the non-steroidal AI arm. But it was a little less likely for the patients in the ribociclib arm to develop bone disease compared to the non-ribociclib arm and so forth.
It seems to be the typical development of metastatic disease that we see in hormone receptor-positive breast cancers. They did not seem to be a major difference compared to what we have seen in patients that have not been exposed to a prior CDK4/6 inhibitor.
NATALEE: DDFS Summary by Nodal Stage
As looking at nodal stage, again, important to show that even patients with N0 disease seem to get a benefit from the use of ribociclib. These were higher risk node-negative disease patients, but still had a numerical benefit that suggested that we should be giving ribociclib to these patients.
[01:36:17]
lidERA: Phase III Trial of Adjuvant Giredestrant vs SOC ET for ER+ HER2-Negative EBC
Probably one of the highlights of SABCS was the presentation of the lidERA trial. This was the first SERD adjuvant trial to be presented. So far, we have had tamoxifen, we have had aromatase inhibitors being given in the adjuvant setting. We shied away from fulvestrant because of the intramuscular administration.
Now with the oral SERDs, this brings us into a totally new era where a lot of these trials are evaluating oral SERDs in the adjuvant setting. There is the first one to have data.
This is a trial that included stage I to III breast cancer patients. Stage I patients had a little bit of a higher risk than your typical stage I breast cancer patients. Patients were randomized to standard of care endocrine therapy or giredestrant. This was given for the 5 years that we typically give these drugs. Primary endpoint was invasive disease-free survival.
When looking at the characteristics of the patients, well balanced between the arms. I just want to point out here that the majority of patients on the trial had stage II or III disease. Only 12% or 13% of patients had stage I breast cancer. This is important because this is the type of patient that was not included in the adjuvant CDK4/6 inhibitor trials because we are always going to be struggling once assuming giredestrant gets approved in this setting, are we going to give giredestrant to these patients, or are we going to give a CDK4/6 inhibitor?
lidERA: IDFS (Primary Endpoint)
There is this nice separation of the curve with an improvement in invasive disease-free survival favoring the arm that received giredestrant with a hazard ratio of 0.7, a positive P value. There did not seem to be a difference in efficacy whether the control arm received an aromatase inhibitor or tamoxifen.
I will point to the fact that the patients that had stage II and III disease clearly had a benefit from giredestrant, but not enough patients with stage I breast cancer included in the trial to show any benefit, although the trend was favoring giredestrant here. And all the other subsets seem to be again favoring the use of giredestrant compared to the standard of care endocrine therapy.
lidERA: Distance Recurrence Free Interval (DRFI) and Interim OS
Distant recurrence-free interval and interim overall survival, very premature. You can see, at least in DRFI, a hazard ratio of 0.69 favoring giredestrant. Even in overall survival, even though this is premature, there is a trend to improvement with the use of giredestrant. This is going to be a trial that we are going to be seeing several other updates in the subsequent years that will help a little bit more in solidifying these results.
lidERA: Safety Summary
Now, as far as safety, you have seen the safety of oral SERDs in the metastatic setting. This did not really change what we have seen previously. Well tolerated agent with a favorable toxicity profile. No major difference between the control arm and the giredestrant as far as toxicities.
Most importantly, when looking at treatment discontinuation, 5% in the giredestrant arm compared to 8% in the standard of care endocrine therapy arm.
Now what are the potential adverse events? Relatively similar to what we have seen in the metastatic setting, there is some arthralgias, some hot flashes. When looking at musculoskeletal disorders, again, there is a suggestion that there might be a little less with giredestrant compared to standard of care endocrine therapy but relatively similar in rates compared to standard of care endocrine therapy.
Now there is some bradycardia that we have also seen with some other oral SERDs. This tended to be mostly grade 1 subclinical, but something to keep in mind. As far as venous thromboembolic events, no difference. Very, very small rate between the arms.
This brings us to the SOLTI-2104 trial. Now, as you have seen with all of these oral SERDs, we are using them in patients that are postmenopausal. Same with fulvestrant. The question has always been, why do we not use them in premenopausal patients since the mechanism of action is not really similar to what we have seen with aromatase inhibitors?
One of the concerns with oral SERDs, especially when we try to use them in premenopausal patients, is the development of ovarian cysts because of the increase in estradiol levels. This was an attempt by the French group to look at elacestrant in premenopausal patients, with or without triptorelin, to see whether it is safe but also whether it is efficacious.
What we do not see very commonly, they looked at complete cell cycle arrest. This was defined as a Ki67 of less than 2.7%. They gave elacestrant or elacestrant plus triptorelin for a 5-week period. This was a window trial. They gave that to patients that had been recently diagnosed with HR-positive early-stage breast cancer. Gave elacestrant or elacestrant-triptorelin and then patients proceeded to surgery after 5 weeks of therapy.
Now, 5 weeks may not be enough time to look at ovarian cysts, but it is enough time to look at, at least, preliminary efficacy from this approach. When looking at that complete cell cycle arrest rate, there is a pretty nice rate of cell cycle arrest happening in patients receiving elacestrant, whether they received it with or without triptorelin, did not really seem to make a difference.
The Ki67 change was 62% in elacestrant and 72% in the elacestrant plus triptorelin arm. Again, these were not supposed to be comparators between the 2 arms, but just present some preliminary data. Then there was a change in ER levels which went down and no real major change in the PR levels.
Something else that we are looking at is also how are these tumors evolving. Many of them are starting out as luminal A tumors. Once you give them therapy, do these tumors continue to be luminal As? Do they change, and how about the luminal B tumors? The majority of the luminal A tumors remain luminal As, and many of those luminal Bs become luminal A while exposed to the use of elacestrant.
They looked at some gene expression, and there was down regulation of several genes that we would have been expecting to.
There is also a decrease in the PAM50 recurrence scores, which is also suggesting that there is a benefit from using elacestrant even in premenopausal patients.
Now moving on to a trial that was presented initially at ESMO, very interesting complicated clinical trial that I feel will be changing our standard of care. There was some updated results at SABCS as well.
This is the DESTINY-Breast11 trial. This is a trial in patients that have early-stage HER2-positive breast cancer. They have high-risk features. This was defined as either clinical T3 or more and N0 to N3, or clinical entity as long as they had at least N1 disease or inflammatory breast cancer.
These patients were randomized into 3 arms: T-DXd followed by THP therapy, and T-DXd was given for 4 cycles; T-DXd monotherapy for 8 cycles; and then dose dense AC followed by THP, which was considered the standard of care arm.
Now the T-DXd arm was discontinued because it was shown that it would not have a superior efficacy compared to the standard of care AC-THP arm. So, the presentation really focused on T-DXd, followed by THP vs dose-dense AC-THP.
Patients received this treatment neoadjuvantly and then proceeded to surgery.
When looking at the results that were presented at ESMO, there was an improvement that was statistically significant in the ITT population HR-positive and HR-negative population, favoring the T-DXd followed by THP arm. That improvement went from 56.3% pCR rate to 67.3%.
The rates of pCR were higher in the HR-negative patients compared to the HR-positive, and we have seen this in many other clinical trials. So, this is not a surprise. This is really showing us that 4 cycles of T-DXd followed by THP can improve outcomes for our patients compared to standard of care acTHP therapy.
The updates from SABCS looked at interstitial lung disease. Obviously, when we are giving T-DXd in the metastatic setting, we see anywhere between 10% to 15% rate of ILD. In the adjuvant curative setting, this becomes even more important to address.
The rates of T-DXd ILD were relatively low, 4.4% in the T-DXd arm, and surprisingly to me, 5.1% in the dose-dense AC-THP arm. Most of that ILD was grade 2 with very little grade 3 ILD, although 1 patient from each arm had grade 5 ILD. The median time of onset was 82 days with T-DXd and 77 days with dose dense AC-THP. That is relatively similar to what we see in the metastatic setting as well. It seems from this analysis that giving 4 cycles of T-DXd is producing much lower rates of ILD compared to what we have seen in the metastatic setting, with much longer exposure to T-DXd.
When looking again at treatment discontinuation and the reason for treatment discontinuation, ILD was a big reason here. There definitely were also some treatment interruptions because of ILD.
As far as steroidal use, as you can imagine, there was more steroidal use in the T-DXd arm compared to the dose-dense AC-THP arm because of the ILD pneumonitis: 50% of patients with grade 1 ILD received a corticosteroid, compared to only 16%. Then with higher rates of ILD, the use of corticosteroids was much higher.
As far as other AEs and management, there was more left ventricular dysfunction seen in the dose-dense AC-THP arm compared to T-DXd. That is pretty expected. There was more nausea and vomiting in the T-DXd arm. When looking at the use of antiemetics, they were more likely to be using 3 or more antiemetics in the dose-dense AC-THP arm. Now this is important because these trials are global trials. The standards that we have in the US as far as using antiemetics are not the same as the standards that are being used in the rest of the world. We know that T-DXd is considered a highly emetogenic regimen. We should be using preferably 4 antiemetics, including olanzapine for our patients. This is not standard of care in many other parts of the world. So, this is what is affecting the rates of nausea and vomiting in these global trials.
As far as peripheral neuropathy, it was more common with T-DXd, but those events were relatively low grade.
Virginia or Sara, any final comments or extra details about any of the data we have looked at or final thoughts about San Antonio?
Dr Kaklamani: I was actually going to ask how you interpret DB-11 and 05 and what you are planning on doing in practice, assuming this agent will get approved in the neoadjuvant and adjuvant setting?
Dr Tolaney: Not an easy question. I am not sure that there is a correct answer. Obviously, DB-11 gives us the option to give sequentially 4 cycles of T-DXd followed by THP, and results in a significant improvement in pCR compared to our normal approach. One could argue that control arm was not maybe ideal compared to what we are using in the USA, but to be honest, we know AC-THP performs just as well as TCHP, so I did think this was a significant improvement.
Whereas on DB-05, T-DXd really did a lot better than T-DM1 and the residual disease high-risk setting. The way I have been thinking about it is that if you give it pre-op to a really high-risk patient, you can improve pCR and get away with just 4 cycles of T-DXd. The rates of toxicity were a lot less than I was anticipating with pre-op T-DXd to only see a little over a 4% ILD rate. In fact, half of that was driven by the taxane component is actually pretty impressive.
If I had a really high-risk patient in the upfront setting, I probably would want to give sequential therapy. For someone who maybe had lower risk disease upfront and you did not give them T-DXd, then certainly if they end up with a lot of residual disease, node-positive disease, and you can always give them T-DXd out back, it is a lot of T-DXd in a DB-05 setting, 14 doses, almost 10% ILD rate.
If you could avoid that, that would be nice and still achieve excellent outcomes. But in truth, I think what we all feel is we want a biomarker because not everyone needs a T-DXd. If we could select the people get away with THP upfront, that would be great. Then they do not need any T-DXd at all the whole time and you have cured the majority of your HER2-positive patients. So hopefully we will get there. It is a complicated setting, but nice to have so many choices.