Let us move in now and jump into the data. We have, I believe, a total of 15 trials that we are going to cover. So, it is going to be quite a whirlwind. Hopefully this data is going to be super interesting and relevant to your patient practice.

 

Let us get started in the first-line setting. For the majority of patients globally, the standard of care in the first-line setting is offering endocrine therapy with a CDK4/6 inhibitor. We have all seen for many of our patients, we have some folks who do extraordinarily well with this regimen and have many years of disease control.

 

It is tricky to know from the very beginning who is going to be in that category of long-term or very long-term response and who might have earlier progression.

 

This pooled analysis of the MONALEESA trials was designed to try to identify predictors of who will have a long-term response, which was defined as 4 or more years of disease control, or a very long-term response, which was 5 or more years of disease control. Just as a reminder, the MONALEESA trials and the ones included here were MONALEESA-2, 3, and 7 were all very large phase III trials that looked at endocrine therapy plus or minus ribociclib for advanced ER-positive disease.

 

When pooling these trials and looking at outcomes, it was found that 23% of patients, so almost a quarter, had long-term response, and about 17% had very long-term response. This analysis was designed to focus on these patients with the very good benefits.

 

[00:28:02]

 

MONALEESA LTR Analysis: Patient Characteristics

 

These are patient characteristics of those included in the pooled analysis, and in general, patients with long-term or very long-term response rates did not differ significantly by age, BMI, or ECOG performance status. Additionally, the long-term response rate was similar between patients who were premenopausal vs those who were postmenopausal. Remember, premenopausal patients were all getting LHRH agonist as well.

 

[00:28:30]

 

MONALEESA LTR Analysis: Disease Characteristics

 

In this slide, we are looking at the disease characteristics, which may be predictive of those having longer or very long-term disease control. Some of the findings that suggested a greater likelihood of control, included those with fewer metastatic sites. Patients who had 3 or more metastatic sites were less likely to have long-term control, including patients who had liver metastases.

 

Importantly, there were similar rates of long-term and very long-term response in patients with de novo or recurrent disease, patients with lung involvement or patients with bone-only disease, which is interesting because we sometimes think about some of these categories as predicting the patients will do better, but here actually they did fairly similar.

 

I would also add to this that whether patients had a treatment-free interval of less than 12 months or more than 12 months, it was fairly balanced whether or not patients would have long-term disease control.

 

[00:29:28]

 

MONALEESA LTR Analysis: Biomarker Analyses

 

Thinking about biomarkers, there is a fairly expansive analysis done looking at molecular predictors of long-term or very long-term response. In general, this matches what we think of as biologic predictors of poor response. This includes patients who are more likely to be TP53 positive were less likely to have long-term response. Patients with less expression of CCNE1 were more likely to have long-term response. Patients who are luminal A were more likely to have long-term response.

 

The biologic features that we think of as suggesting a favorable tumor biology were aligned with patients who experienced prolongation of disease control.

 

In general, we can take away from this that when we are starting patients on first-line therapy with endocrine and CDK4/6 inhibitor, some of the clinical pathologic features that we think of as being predictive of patients doing well, including less burden of metastatic disease, less liver involvement and molecular features including less P53 or perhaps less basal like, these all would predict that patients will have longer periods of disease control on CDK4/6 inhibitor, including 1 out of 4 patients with at least more than 4 years of disease control.

 

[00:30:53]

 

ELEVATE: Phase II Trial of Elacestrant + Everolimus or Abemaciclib in ER+/HER2- Locally Advanced or MBC

 

Now let us move on to one of the very hot areas of management in metastatic ER-positive breast cancer, which is exploration of the oral SERDs. This has been an incredibly active area of interest with 4 lead oral SERD agents, which have been in very active development.

 

These are oral therapies that are designed to target the estrogen receptor, decreasing expression of estrogen responsive elements and leading to degradation of the estrogen receptor. A very profound way to target the estrogen receptor, in contrast to, for example, an aromatase inhibitor, which is just depleting the body of estrogen.

 

These agents may also have preferred activity in the setting of ESR1 mutations, which can lead to constitutive activation of the estrogen receptor and is a mechanism of resistance. We are going to go through the data looking at all 4 of these agents, many of which are updates on studies that we have seen throughout 2025.

 

We are going to start with the ELEVATE study, which is looking at elacestrant. Elacestrant is one of our FDA-approved oral SERDs approved as monotherapy in patients who are pretreated whose cancers have an ESR1 mutation.

 

The ELEVATE study is a platform phase I/II umbrella trial that is designed to look at elacestrant in combination with a targeted partner. The report that was presented at San Antonio was specifically looking at elacestrant in combination with everolimus and in combination with abemaciclib: 50 patients with everolimus, 60 patients with abemaciclib.

 

Patients who enrolled on ELEVATE had pre-treated disease, and could have had 1 or 2 prior lines of endocrine therapy, with or without CDK4/6 inhibitor, and no prior chemotherapy in the advanced setting. Prior fulvestrant was allowed.

 

The primary phase II endpoint was progression-free survival.

 

[00:32:48]

 

ELEVATE: Baseline Characteristics

 

Here are the baseline characteristics of the patients in these 2 cohorts. I will point out that the majority of patients had visceral metastases. There was a median of 1 prior line of endocrine therapy for advanced disease. There is a little imbalance in prior exposure to CDK4/6 inhibitor.

 

In the everolimus arm, all the patients had prior CDK4/6 inhibitor, and you can see the distribution here. In the abemaciclib arm, only about half of the patients had prior CDK4/6 inhibitor; no patients with prior abemaciclib, of course.

 

About 50% in the everolimus arm, 30% in the abemaciclib arm had prior fulvestrant.

 

[00:33:30]

 

ELEVATE: PFS in All Participants and Key Subgroups

 

Here is the primary endpoint of progression-free survival in these 2 groups of patients. In the elacestrant and everolimus arm, the PFS was 8.3 months, and in the elacestrant and abemaciclib arm, the PFS was 14.3 months.

 

Looking across subgroups shown in the bottom of this slide, you can see that for the everolimus arm across all of the subgroups, we can see that the benefit of the combination is very consistent. This is included in patients with and without ESR1 mutation and with and without PI3 kinase mutation.

 

In the abemaciclib arm, we can also see this is preserved in patients with no prior fulvestrant and patients with no prior endocrine resistance.

 

In general, we see quite consistently in all of the trials that are combining an oral SERD with a targeted partner, a fairly robust progression-free survival with numbers almost always consistently more than 6 months of disease control.

 

The elacestrant and abemaciclib is quite striking at 14 months, although, again, it is important to remember that half of these patients were naive to CDK4/6 inhibitors, and we would expect a pretty robust response if they have not seen that category of drugs before.

 

[00:34:51]

 

ELEVATE: Safety of Elacestrant + Everolimus

 

Another important point when we consider the use of a combination of an oral SERD and a targeted partner, is that, in general, the oral SERDs are extraordinarily well tolerated and they contribute very little toxicity to the patient experience. Most of the toxicity seen in these combinations reflect the targeted partner. We do see this in the ELEVATE study.

 

The treatment-emergent adverse events seen in the combination with everolimus are fairly characteristic for everolimus, nausea, diarrhea, fatigue. We see stomatitis and rash. These are really the contribution of the mTOR inhibitor, not the oral SERD.

 

In general, there was very little toxicity leading to withdrawal of drug. Notably, there was also no bradycardia or photopsia. These are toxicities we will get back to later.

 

[00:35:43]

 

ELEVATE: Safety of Elacestrant + Abemaciclib

 

This is a similar data with abemaciclib. Again, we can see that the tolerability really reflects the toxicities we know about from abemaciclib, including 83% of patients with diarrhea. That is a pretty consistent number with abemaciclib, nausea, fatigue, again, common toxicities with abemaciclib.

 

[00:36:02]

 

EMBER-3 Update: Imlunestrant ± Abemaciclib vs SoC ET in ER+/HER2- Advanced Breast Cancer

 

Let us move on to look at another combination of oral SERD with targeted partner. This is an update from the EMBER-3 study. This is a very important phase III study that is looking at the oral SERD, imlunestrant, with or without abemaciclib or vs standard of care endocrine therapy. This is a 3-arm randomized study. This included patients who had had up to 1 prior line of endocrine therapy in the metastatic setting with or without CDK4/6 inhibitor. No prior chemotherapy.

 

Patients were randomized to 1 of 3 arms. There is imlunestrant monotherapy. There is a standard of care endocrine therapy arm. Both of those are monotherapy. Then there is a third arm that is a combination, imlunestrant with the CDK4/6 inhibitor, abemaciclib.

 

This trial has 3 primary endpoints looking at progression-free survival between the monotherapy arms, imlunestrant vs standard of care in the ITT population, as well as in the population of patients whose tumors have ESR1 mutations, and a comparison of PFS between imlunestrant and the combination of imlunestrant and abemaciclib.

 

The updated data we saw at San Antonio was looking at updates in the clinical endpoints, including progression-free survival and overall survival, as well as an exploratory endpoint looking at molecular response.

 

[00:37:33]

 

EMBER-3 Update: PFS (Primary Endpoint)

 

In terms of primary endpoints, this is updates for progression-free survival. On the left, we can see in the ESR1 mutation population, patients who received imlunestrant had a significant prolongation in progression-free survival from 3.8 months with standard of care monotherapy to 5.5 months with imlunestrant. Hazard ratio of 0.62. This is very consistent with prior data. This is the data that led to the recent FDA approval of imlunestrant as monotherapy for pretreated patients whose cancers have an ESR1 mutation.

 

There was also an update in the combination comparison, showing us the patients who received the combination of imlunestrant and abemaciclib had practically a doubling in progression-free survival compared to imlunestrant monotherapy from 5.5 months to 10.9 months. Hazard ratio, 0.59. Also fairly consistent with prior data.

 

[00:38:30]

 

EMBER-3: PFS by Subgroups I+A vs I

 

Now, importantly, looking at the subgroups, this is looking at the combination imlunestrant-abemaciclib vs imlunestrant alone. It is important to note that the benefit of progression-free survival was seen whether the cancer had an ESR1 mutation, an improvement from 5.5 to 11.1 months, or if the cancer did not have an ESR1 mutation, 5.5 months to 9.2 months.

 

Whether or not ESR1 mutation was present, the combination of imlunestrant and abemaciclib was active. This does suggest to us, and we have now been seeing this consistently in the trials, that when a targeted partner is added to the oral SERD, meaning that you are targeting the estrogen receptor pathway, and you are also targeting a crosstalk resistance pathway, that you can overcome any restriction on having an ESR1 mutation in the cancer. We do see evidence of this here.

 

Now, other important subgroups included the CDK4/6 pretreated patients where the benefit is preserved. We also see benefit regardless of whether a PIK3CA mutation was present.

 

On the bottom, you will see the co-mutated population. That means having both ESR1 and PI3 kinase pathway mutation. Generally, that is a pretty small group. It is about 15% of all patients, but it is a situation where we might be wondering which drug should I reach for something targeting ESR1 or something targeting PI3 kinase.

 

Here we see a nice preservation of benefit 5.5 to 12 months, suggesting to us that it is very reasonable and appropriate to go after the ESR1 mutation with the use of an oral SERD in this setting.

 

[00:40:10]

 

EMBER-3: PFS in CDK4/6 Pretreated Patients by Subgroups

 

This is looking at the subgroup data, specifically in patients with prior CDK4/6 pretreatment. This was about 60% of patients in the trial. Again, we see preservation of benefit across all of these subgroups.

 

[00:40:24]

 

EMBER-3 Update: Interim OS (Secondary Endpoint)

 

There was an update on interim overall survival, which remains immature, yet there is greater maturity compared to the last report. We can see that for the monotherapy comparison, the hazard ratio for overall survival is 0.60. Not yet statistically significant, but trending favorably.

 

Also importantly, in the comparison of the imlunestrant-abemaciclib vs imlunestrant, now the hazard ratio is 0.82. This is at 33% maturity.

 

When we first saw the EMBER-3 data, this was at 15% maturity and the overall survival hazard ratio was trending in a somewhat unfavorable way, which is not surprising when you only have 15% of the data. Now, as more data is coming in, we are seeing a favorable trend. Of course, we will need to continue to monitor this.

 

[00:41:14]

 

EMBER-3 Update: OS in Patients With ESR1m by Subgroups

 

This is looking at overall survival in subgroups of the population of patients with ESR1 mutation. We can see very consistently favorable hazard ratio in all of these prespecified subgroups.

 

[00:41:28]

 

EMBER-3: TTC in Patients With ESR1m (Exploratory Endpoint)

 

Time to chemotherapy was an exploratory endpoint. We can see in the monotherapy comparison, the need for chemotherapy was delayed using imlunestrant instead of standard of care endocrine therapy. It was delayed by close to 6 months, which is very clinically meaningful.

 

[00:41:46]

 

EMBER-3 Update: PFS by MR Status (Exploratory Endpoint)

 

This was an exploratory analysis looking at progression-free survival by molecular response. ctDNA was gathered at baseline and at cycle 2, day 1, looking at a decrease in allele fraction for ESR1 mutation. A molecular response was defined as having at least a 50% reduction in the allele fraction.

 

When we look at the changes in the allele frequency, the VAF at cycle 2, if we look at, particularly in the patients with ESR1 mutation detected, we can see very profound reductions in the patients who received the oral SERD imlunestrant compared to those who received standard of care endocrine therapy. In particular, those who experienced a molecular response, if you are looking at the top, had an improved progression-free survival compared to those who did not experience a molecular response.

 

This is really exciting data because it suggests to us perhaps there is a way for us to know as soon as cycle 2, day 1, who is going to do well on this therapy and who is not doing well on this therapy. It begins to set up a way, perhaps in the future, that we would get some early readouts to know whether we are going in the right direction with a treatment and should continue, or whether it is going to be not as favorable and we should change course.

 

It is also important, just from a pharmacodynamic point of view, to show us that the oral SERD is hitting the target.

 

[00:43:12]

 

EMBER-3 Update: Safety Summary

 

The safety seen in EMBER-3 was very consistent with what had previously been seen. Again, the safety is mostly characteristic of abemaciclib in the combination arm. Imlunestrant monotherapy is extremely well-tolerated drug with practically no grade 3 toxicity.

 

[00:43:29]

 

SERENA-6 Update: Camizestrant + CDK4/6i for Emergent ESR1m in Patients With HR+/HER2- ABC

 

Now let us move on to another oral SERD study. This is SERENA-6. I call it a one-and-a-half-line study. It is not first-line. It is not second-line. It is living in the middle. This was a 2-step study using the oral SERD, camizestrant.

 

Step 1 enrolled patients who had started first-line therapy for metastatic hormone receptor-positive, HER2-negative disease with an aromatase inhibitor and a CDK4/6 inhibitor. After 6 months of disease stability, they entered screening for emergence of an ESR1 mutation.

 

What was being looked for was detecting the mutation, so an emerging resistance mutation, but not seeing or seeing this prior to actual clinical progression on a scan. So, trying to find a window when resistance is developing in the cancer, but the cancer has not yet progressed.

 

The screening step, which enrolled over 3,000 patients, identified 315 patients who moved on to step 2 of the study, where they were randomized to switch their endocrine therapy from aromatase inhibitor to the oral SERD, camizestrant, and continue CDK4/6 inhibitor and add a placebo, or continue AI and CDK4/6 inhibitor and add a placebo.

 

Primary data from SERENA-6, which is a positive study for the primary endpoint of progression-free survival, was presented at ASCO plenary this year. At San Antonio, there was updated clinical endpoints including PFS1, PFS2 and ctDNA dynamics.

 

[00:45:00]

 

SERENA-6 Update: Survival and ESR1m ctDNA Outcomes

 

Let us take a look. Here is the updated survival. We can see that progression-free survival, which was positive at the first look remains positive with an improvement from 9.2 months with the AI arm to 16 months with the camizestrant arm.

 

PFS2 has greater maturity. It is now at 84%. This is a favorable result with an improvement of about 6 months in PFS2 and a hazard ratio of 0.56, although the P value remains below the threshold for significance, that has been pre-specified.

 

Additionally, there was about a 6-month improvement in chemotherapy or ADC-free survival, again, a very clinically relevant endpoint.

 

[00:45:51]

 

SERENA-6 Update: Safety Summary

 

This slide is titled Safety Summary. It is actually the ctDNA dynamics. Again, similar to EMBER-3, this is really interesting, showing that looking at ESR1 mutation allele frequency in the patients who received camizestrant, there is, on median, 100% decrease in ESR1 mutation frequency in that arm.

 

In comparison, in the aromatase inhibitor arm, there is an increase. In fact, a quarter of patients had a 500% increase in ESR1 mutation status. This is showing us molecularly what use of the oral SERD is doing in terms of targeting the ESR1 mutation.

 

[00:46:33]

 

SERENA-6 Update: Summary of Visual Effects

 

There was a poster presented looking specifically at visual effects. Camizestrant is one of the oral SERDs which has a specific toxicity associated with it called photopsia, which means that patients can see flashing lights, halos, afterimages on the periphery of their vision under low light conditions. This is something which tends to be very brief and not bothersome to patients. It does not affect their actions, but it is something that we want to learn more about because it is a new toxicity for us.

 

This was a deep dive into visual effects in SERENA-6, first of all, showing us that of all the study population in terms of grouping all ocular side effects, about 30% of patients in the camizestrant arm had an ocular side effect, compared to 16% with AI. This is important because if you give AI, patients are still experiencing ocular side effects and here we see 77% experienced photopsia, which is not something we normally think about with AI, but it can happen; 20% experienced photopsia in the camizestrant arm.

 

[00:47:36]

 

SERENA-6 Update: Change From Baseline in Visual Acuity

 

Further analysis has shown there was no change in visual acuity in those who received camizestrant. Again, the photopsia is very brief. It does not impact patient activity. I think we can feel reassured by this data and we could reassure patients if they are receiving camizestrant.

 

[00:47:53]

 

evERA: Clinical & Biomarker Subgroups of Giredestrant + Everolimus in ER+/HER2− ABC and Previously CDK4/6i

 

Moving on to evERA, another combination study. This is looking at giredestrant and everolimus vs standard of care endocrine therapy and everolimus in patients who are pre-treated, all of whom had a prior CDK4/6 inhibitor. No prior chemotherapy.

 

Giredestrant is an oral SERD. This study was previously presented at ESMO, and there was updated data presented at San Antonio as well as biomarker subgroups.

 

[00:48:22]

 

evERA Subgroup Analysis: PFS in ITT and ESR1m

 

This is actually the ESMO data. It was represented at San Antonio showing that this was a positive study, that in both the ESR1 mutant and the ITT populations, there was a substantial prolongation in progression-free survival with the use of giredestrant over standard of care endocrine therapy.

 

There was a subgroup analysis looking at the ESR1 no mutation detected population, which showed no substantial difference in progression-free survival, but a favorable trend for overall survival.

 

[00:48:54]

 

evERA Subgroup Analysis: ORR and DoR in ESR1m and ITT Populations and Patients Without ESR1m Detected

 

There was subgroup analysis presented at San Antonio showing us that overall response rate was essentially doubled in all groups: ESR1-mutant, ITT, and those without an ESR1 mutation. The responses were prolonged with again a doubling of median duration of response with the use of giredestrant compared to standard of care endocrine therapy.

 

[00:49:17]

 

evERA Subgroup Analysis: PFS in Subgroups

 

This was the subgroup analysis presented at San Antonio, showing us that in patients with and without PI3 kinase mutations and in patients who are co-mutated with the ESR1 and the PI3 kinase or PI3 kinase pathway mutation, we see a preserved benefit from the use of giredestrant.

 

[00:49:38]

 

evERA Subgroup Analysis: PFS by PIK3CAm and PIK3CA/AKT1/PTEN Alteration Status

 

Again, looking at this in terms of a forest plot, we can see that this is a significant in both patients with ESR1 mutation and the ITT population. Both of these are the primary endpoint populations. The benefits in ESR1 not detected group are trending favorably, although not significant in this setting.

 

[00:49:59]

 

evERA Subgroup Analyses: PFS by Duration of Prior CDK4/6i

 

Additionally, benefits were seen regardless of duration of prior CDK4/6 6 inhibitor, here divided by less than 12 months vs greater than 12 months. This is an effort to try to identify who has more or less endocrine sensitive disease. We do know with an oral SERD such as elacestrant, we prefer to offer this to patients who have prior prolonged duration of disease control with endocrine therapy in an effort to identify endocrine sensitive patients. Here we see that the benefit is consistent, whether or not the prior duration was less than or more than 12 months.

 

[00:50:36]

 

evERA Subgroup Analyses: Safety Summary

 

Safety was stable and consistent with prior reports. We can see that, in general, that the toxicity profile seen with giredestrant-everolimus is primarily driven by everolimus. There is very little toxicity contributed by giredestrant.

 

Rates of discontinuation were fairly low, 8.2% in the combination arm. There was some grade 1 bradycardia, which is seen with some oral SERDs, but this generally is asymptomatic, does not require any intervention. There was no photopsia seen.

 

[00:51:09]

 

PIKALO-1: Phase I/II Trial of PI3Kα Inhibitor LY4064809/STX-478 (Tersolisib) for HR+/ HER2- PIK3CA-Mutant ABC

 

We are now going to move towards PI3 kinase inhibitors. We saw data from the PIKALO-1 study. This is a study of a new drug called tersolisib. This is what we call a mutant-specific PI3 kinase inhibitor. This is an important category of drugs, because the idea with these drugs is to target the mutant PI3 kinase in the tumor and spare the wild-type PI3 kinase in our normal liver and muscle cells by sparing this. This is an effort to reduce the toxicities that we can see with traditional PI3 kinase inhibitors, including hyperglycemia, which has been a challenging toxicity to manage in clinic.

 

This is a study that is looking at tersolisib as monotherapy or in combinations, primarily looking at safety but also looking at clinical activity. This was for patients with pretreated disease. Notably, they could have a hemoglobin A1C up to 8. They received either tersolisib monotherapy in combination with fulvestrant or as a triplet with a CDK4/6 inhibitor.

 

[00:52:15]

 

PIKALO-1: Baseline Characteristics

 

This is the baseline characteristics of patients in this study. There were a number of patients who had pre-diabetes or even type 2 diabetes, and there was a median of 2 prior lines of therapy. Very few patients had prior PI3 kinase inhibitor.

 

[00:52:32]

 

PIKALO-1: Pharmacokinetics and Tumor Response

 

Here is the pharmacokinetics and tumor response. Just focusing on the response, we can see across the board as monotherapy a response rate of 18%. That increases to about 25% to 30% when used in combination, and a disease control rate in the combination of 80% or more. So a quite active agent for this population of patients with PI3 kinase mutations.

 

[00:52:55]

 

PIKALO-1: Safety Summary

 

In terms of safety, I want to focus on the hyperglycemia. There were rates of hyperglycemia around 25% all grade, but there was practically no grade 3 hyperglycemia. This included the patients who had prediabetes or actual diabetes. This is really encouraging considering what we have seen with other PI3 kinase inhibitors, which can cause hyperglycemia in an even more hemoglobin A1C restricted population.

 

There are some relatively low level rates of diarrhea and rash, but overall this appears to be a very well-tolerated drug.

 

[00:53:32]

 

PIKALO-1: Impact on Glucose Metabolism and ctDNA

 

A deeper dive into hyperglycemia showed that there was minimal impact on mean fasting glucose for patients with or without prediabetes. That also in their exploratory correlative science, there was a decrease in PI3 kinase mutant ctDNA variant allele fraction at cycle 2, which is, again, as we have seen, a very favorable endpoint to identify.

 

Stay tuned for more from tersolisib. This is entering phase III trial as a triplet. If you have that trial open, I encourage you to support it, because this may be the next new thing for our patients who have PI3 kinase mutations.

 

[00:54:10]

 

VIKTORIA-1 Update: Gedatolisib (PAM Inhibitor) + Fulvestrant ± Palbociclib as 2L in Patients With HR+/HER2-/PI3KCA WT ABC

 

Last abstract in my set will be VIKTORIA-1, that is looking at a drug, gedatolisib, which is a PAM inhibitor. That is PI3 kinase, AKT, mTOR pathway inhibitor.

 

VIKTORIA-1 is a study for pre-treated patients, no prior chemotherapy. Patients can be in 2 groups. One group in VIKTORI-1 has a PI3 kinase mutation. We are still awaiting data from that part of the trial. What we have seen reported both at ESMO and now again at San Antonio is the PI3 kinase wild-type group.

 

These patients are randomized to receive gedatolisib and fulvestrant, so a doublet; gedatolisib, palbociclib and fulvestrant, a triplet; both compared to fulvestrant monotherapy. I will point out that gedatolisib interestingly is an IV medication. It is given 3 weeks on, 1 week off.

 

Additionally, this study had a more restrictive hemoglobin A1C requirements, could not be more than 6.4%.

 

[00:55:14]

 

VIKTORIA-1 (Update): Efficacy Summary

 

In terms of an efficacy summary, we have seen both at ESMO and at San Antonio, that the doublet and the triplet show statistically significant improvements over fulvestrant monotherapy. This was seen regardless of the duration on prior line of therapy, whether that was 6, 12, 18 or 24 months. No significant difference if bone-only vs non-bone only.

 

[00:55:41]

 

VIKTORIA-1 (Update): Additional Safety

 

There was also additional safety summary, a deeper dive into hyperglycemia. We can see here that rates of hyperglycemia reassuringly were low. Looking at mean fasting glucose over time, we can see this remains very stable, which again is very favorable considering what we have seen with other PI3 kinase inhibitors.

 

[00:56:01]

 

VIKTORIA-1 (Update): PROs

 

There was progression-free survival data that was presented showing preserved progression-free survival vs fulvestrant monotherapy.

 

We will end with the ER-positive section here. A tremendous amount of data that was presented, much of this is updates, but many new agents and new combinations which hopefully will enter our clinic soon.

 

We are going to pivot now and move to HER2-positive breast cancer. I am going to turn this over to Sara.

 

[00:56:35]

 

HER2CLIMB-05: Tucatinib vs Placebo Added to HP + as First-line Maintenance Therapy for HER2+ MBC

 

Dr Sara Tolaney (Dana-Farber Cancer Institute): Thanks so much, Erica. That was a tremendous overview of a lot of really exciting data in the ER-positive setting. We also were really excited to see data in the metastatic HER2-positive setting in the HER2CLIMB-05 study. These data were highly anticipated, as we had seen a press release come out prior to San Antonio.

 

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.

 

[00:57:18]

 

HER2CLIMB-05: Baseline Characteristics

 

When we look at the patients that were enrolled into this study, you can see that about half of the patients had ER-positive disease, half ER-negative. About 12% actually 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 in terms of 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.

 

You can also see that 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. So a lot more de novo patients here.

 

[00:58:17]

 

HER2CLIMB-05: Investigator-Assessed PFS (Primary Endpoint)

 

When we look at the data, though, 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. Again, a little surprising that these numbers are lower than we anticipated.

 

[00:59:08]

 

HER2CLIMB-05: PFS by Subgroup

 

When you look at the relative benefit across various subgroups, you do see it as very consistent, again, across all of these subgroups.

 

[00:59:16]

 

HER2CLIMB-05: PFS by BICR and Hormone Receptor Status

 

What I think was really 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.

 

Here you can see in the HR-negative subset, the hazard ratio is about 0.55. When you look at the HR-positive subset, you see 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.

 

[00:59:54]

 

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 just caution you that CNS events are lower in this upfront setting.

 

With the follow up time, 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. While there is a nice trend favoring fewer CNS events at time of progression, both in the ITT and patients with brain mets at baseline, the differences are numerically quite tiny. I would just interpret this with caution at this point that maybe there is a small signal, but we need more time for follow up.

 

OS data is highly immature at this time point, but a very nice trend favoring the addition of tucatinib.

 

I will say I took away from this trial that adding tucatinib to HP maintenance should be practice changing. It is clearly improving PFS across these patients. The question though is how do we integrate it into the first-line metastatic HER2-positive setting where we do have lots of choices.

 

[01:01:03]

 

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.

 

[01:01:28]

 

HER2CLIMB-05: Treatment-Emergent Adverse Events

 

When you look at the overall rate of diarrhea, it was about 70% in the tucatinib arm with about 6% grade 3 events. Looking at the LFTs, you can see that about 25% of patients do get elevated LFTs.

 

[01:01:42]

 

HER2CLIMB-05: Hepatic and Diarrhea Treatment-Emergent AEs

 

They did do a deeper dive into the hepatic and GI toxicity within this trial, again suggesting higher grade toxicities in terms of GI events with tucatinib-based treatment and more discontinuations due to either of these toxicities compared to the placebo arm.

 

When you look at time to onset for hepatic toxicity, you see it is about 40 days and for diarrhea about 50 days.

 

[01:02:10]

 

PATINA CNS Outcomes: Palbociclib + Anti-HER2 + ET in Previously Treated HR+/HER2+ MBC

 

Putting this into context is really 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 actually 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.

 

[01:03:38]

 

PATINA CNS Outcomes: Cumulative Incidence of CNS Progression or Death (All Patients)

 

What we did find was that if you looked at 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%.

 

You see 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, though, that only about 4% of patients had brain mets at baseline in the PATINA trial. Again, they were not screened with mandatory CNS imaging. So, you are seeing a very similar results here.

 

I think intriguing, because we have all wondered what the benefits of CDK4/6 in terms of prevention of brain mets are. Here there is certainly a trend potentially favoring that palbociclib could be impacting that.

 

[01:04:36]

 

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. We just saw 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. So these data were really important to see because it did look at PROs.

 

[01:05:51]

 

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 the 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. Again, that was a little surprising to me personally to see.

 

[01:06:21]

 

DESTINY-Breast09: PRO (Secondary Endpoint)

 

We also saw there were no differences in risk of clinical meaningful deterioration in pain between 2 arms. So similar tolerability. 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.

 

[01:06:46]

 

ASCENT-07: Sacituzumab Govitecan vs CT as First Post–Endocrine Therapy in HR+/HER2− MBC

 

Maybe we will have time for a little bit of discussion, because 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, and hopefully we will have some time to discuss that.

 

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.

 

[01:07:46]

 

ASCENT-07: Previous Therapies

 

When you look at the patients that were enrolled into the trial, you can see that the majority of patients had had prior endocrine therapy with CDK4/6 inhibition, about 90% of patients, which, again, would be consistent with our current practice patterns.

 

[01:08:09]

 

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. You can see 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, though, 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. You could imagine this occurring in clinical practice where you know you are on the control arm and one could think potentially could there actually be bias in the study, where a patient may not have centrally confirmed RECIST progression but wants to move on to an ADC. You did see a little bit of this occurring. Although 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.

 

[01:09:21]

 

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%, again, reflecting, what many of us would anticipate in this study where it is not blinded to drug.

 

[01:09:33]

 

ASCENT-07: Tumor Responses and DoR by BICR

 

You see objective response rates are fairly similar between the 2 arms. You do see that 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.

 

[01:10:00]

 

ASCENT-07: Treatment Exposure and Safety Summary

 

When you look at treatment discontinuation, you can see it is fairly similar between the 2 arms. There were more grade 3 adverse events with sacituzumab compared to chemo.

 

[01:10:11]

 

ASCENT-07: Most Common TEAEs (in ≥20% of Patients)

 

Here you can see 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.

 

[01:10:30]

 

ASCENT-03 Safety Analysis: Sacituzumab Govitecan vs CT in Previously Untreated Advanced TNBC Ineligible for PD-(L)1 Inhibitors

 

What we did not show here, though, was that there was a difference for PFS based on investigator-assessed PFS. That was really intriguing to see. 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 was a study that 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 immune 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).

 

[01:11:59]

 

ASCENT-03 Safety Analyses: TEAEs, EAIRs, and Deaths

 

When we look at the safety analysis, though, we had previously seen that there were more serious adverse events associated with sacituzumab compared to chemotherapy. But one always has to think about whether or not these events are similar based on adjustment for exposure, because certainly patients in the sacituzumab arm are getting longer duration therapy because it was controlling their disease longer than the control arm. In this analysis, they did look at exposure-adjusted analyses.

 

One thing to keep in mind. Again, these data were previously presented at ASCO. 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, really important to do.

 

[01:13:17]

 

ASCENT-03 Safety Analyses: Exposure-Adjusted Incidence Rates

 

When you look at the exposure-adjusted analyses, interestingly, you do see that there are fewer issues with thrombocytopenia, anemia, and neuropathy with sacituzumab compared to chemotherapy. But you do see more in the way of diarrhea related to sacituzumab compared to standard chemotherapy.

 

[01:13:37]

 

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 really that different between the 2 arms, but you do see earlier onset of diarrhea with sacituzumab compared to chemotherapy.

 

[01:13:49]

 

ASCENT-03 Safety Analyses: Management of Neutropenia

 

When we look at use of primary and secondary prophylaxis, it is important to realize that the use of primary prophylaxis did result in a significant decrease in rates of neutropenia. Again, an important reminder for considering utilization, neutropenia was a common reason for consideration of dose modification within this trial as well.

 

[01:14:14]

 

ASCENT-04: Safety Analysis of Pembrolizumab With SG or CT for Previously Untreated PD-L1+ mTNBC

 

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.

 

[01:14:34]

 

ASCENT-04 Safety Analyses: Exposure-Adjusted Incidence Rates

 

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.

 

[01:14:58]

 

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. So at least reassuring from that perspective.

 

[01:15:27]

 

ASCENT-04 Safety Analyses: Neutropenia and Diarrhea

 

Again, with the neutropenia and diarrhea, 2 common side effects with the sacituzumab, when you look at median time to onset, you do see 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.

 

[01:15:49]

 

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.

 

Here at San Antonio, we saw data that specifically focused on the safety analysis.

 

[01:16:21]

 

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. So again, 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.

 

[01:16:46]

 

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. You can see time to onset being about 26 days for stomatitis and about 77 days for ocular surface toxicity.

 

[01:17:31]

 

DATO-Base (Cohort C): Dato-DXd in HER2-Negative MBC With LMD

 

We also saw some other data from Dato-DXd. This was from the DATO-Base trial. We saw the presentation of the cohort that specifically focused on leptomeningeal disease. This trial had 3 different cohorts looking at triple-negative, ER-positive brain metastases and then a separate cohort for LMD.

 

[01:17:51]

 

DATO-Base (Cohort C): Baseline Characteristics

 

These reported data on 10 patients with leptomeningeal disease who had received Dato-DXd. These were patients who could have either had a prior ADC or have been ADC naive.

 

[01:18:05]

 

DATO-Base (Cohort C): Efficacy Summary

 

When you look at the patients, most of these patients had hormone receptor-positive disease, and you can see that the objective response rate was 30% within the leptomeningeal disease, with a median PFS of around 4 months and an OS of almost 5 months. Again, these numbers are super tiny, but 7 patients had had prior ADC treatment compared to 3 who were ADC naive.

 

You can see, as one would expect, that the ADC naive patients do have a much longer PFS of around 6 months for intracranial PFS compared to a little over 1 month for the ADC pre-treated patients.

 

[01:18:41]

 

DATO-Base (Cohort C): Safety Summary

 

When you look at the safety, again, very consistent with what we know that oral mucositis is a common side effect seen in this trial in 40% of patients. Ocular surface toxicities also are seen but not as high as previously reported in TB02.

 

That was a whirlwind tour of the metastatic section. I am going to pass it back to Erica to take us through some of the questions.

 

[01:19:08]

 

Posttest 1

 

Dr Mayer: Thank you so much, Sara. That was amazingly comprehensive and fabulous presentation. Let us return to our questions. You have seen these before, but now you have seen all the data. Let us see how we do on the polling. I am going to read each question again.

 

Based on the safety reports from the phase III ASCENT-03 study of SG vs chemo as first-line for advanced triple-negative breast cancer ineligible for PD-1/PD-L1 inhibitor and the phase III ASCENT-04 study of pembrolizumab with SG or chemo as first-line for PD-L1 positive metastatic disease, I plan to apply these data to current or future management strategies. Please vote.

 

1. Strongly disagree;
2. Disagree;
3. Neutral;
4. Agree; or
5. Strongly agree.

 

Let us vote.

 

In terms of the polling results, we can see that 3 quarters of people are voting agree or strongly agree, which I would propose would be a correct answer.

 

[01:20:34]

 

Posttest 1: Rationale

 

For our rationale, as we just heard from Sara, after adjusting for the longer SG treatment exposure, the rates of treatment-emergent toxicity that led to dose reduction or discontinuation, as well as other toxicities such as anemia, thrombocytopenia, peripheral neuropathy were lower with SG vs chemo in ASCENT-03 and 04. But we know that diarrhea is more common with SG vs chemo.

 

Also, as we just heard, it is very important to use the prophylactic growth factor to avoid neutropenia and in particular avoid the rare but serious situation of life-threatening sepsis. We want to integrate this new safety data into our treatment planning, so patients will do as well as possible. We are using novel agents as safely as possible.

 

Okay, let us move on to our second question.

 

[01:21:26]

 

Posttest 2

 

Based on the data presented at San Antonio from the phase II ELEVATE trial that enrolled patients with advanced breast cancer previously treated with 1 or 2 prior lines of endocrine therapy plus/minus CDK4/6 inhibitor, which of the following agents in combination with elacestrant demonstrated a median progression-free survival of over 12 months? Is it:

 

1. Abemaciclib;
2. Alpelisib;
3. Capivasertib; or
4. Everolimus.

 

Please vote. Here is our answers. The majority of people got the correct answer, which was abemaciclib, with fewer votes for the other options.

 

[01:22:26]

 

Posttest 2: Rationale

 

As we just saw in our presentation of the 2 cohorts from the ELEVATE study, the patients who received elacestrant and everolimus had a median progression-free survival of 8.3 months. Those who received elacestrant and abemaciclib had a median progression-free survival of 14.3 months. The PFS benefit was observed in all subgroups, including visceral disease, no prior fulvestrant, no prior primary endocrine resistance.

 

We do want to note that that abemaciclib population was only 50% CDK4/6 pretreated. So they were particularly sensitive to the use of abemaciclib. Overall, the data from ELEVATE helps support for us the importance of using oral SERD in combination with targeted partner.

 

Let us move on to question 3.

 

[01:23:16]

 

Posttest 3

 

Here is our case. Your patient is a 63-year-old postmenopausal woman with recurrent hormone receptor-positive/HER2 metastatic breast cancer 10 months after finishing adjuvant endocrine therapy. She has 2 bone lesions and 1 lung lesion. She is considering first-line therapy with CDK4/6 inhibitor and endocrine treatment.

 

As you are discussing treatment with her, which of the following results would you tell them reported at San Antonio 2025 from a pooled analysis from the MONALEESA studies would predict long-term response and very long-term response in this setting. Is this:

 

1. Younger patients were more likely to have a favorable response;
2. Patients who had recurrent disease within a year did not have a favorable response;
3. Patients with 3 or more lesions had similar rates of long-term and very long-term response compared to those with less than 3 lesions; or
4. Similar long-term and very long-term response if the treatment-free interval was less than or more than 12 months.

 

Please vote. This one is a little trickier because the data was a little bit more complex. We had votes across the board.

 

[01:24:49]

 

Posttest 3: Rationale

 

The correct answer here was number 4, that the chance of having a long-term or very long-term response was similar if the patient recurred less than 12 months or more than 12 months after completion of adjuvant endocrine therapy. This was seen in this pooled analysis. Long-term and very long-term response were less frequent in patients who had 3 or more metastatic sites and less frequent if there were liver mets present.

 

[01:25:24]

 

Posttest 4

 

Let us move on to our final post-test question. This is from the phase III EMBER trial. Remember, this was a trial that enrolled patients with ER-positive/HER2-negative advanced breast cancer who had progression during or after aromatase inhibitor therapy plus/minus CDK4/6 inhibitor.

 

Which of the following statements most accurately reflects the benefit in terms of median progression-free survival with imlunestrant and abemaciclib vs imlunestrant alone across patient subgroups, as reported at San Antonio? Our choices are:

 

1. Benefit is absent in patients treated with more than a year of CDK4/6 inhibitor;
2. Absent in patients with PI3 kinase pathway alterations;
3. Benefit is observed irrespective of ESR1 mutation status; or
4. Benefit is reduced in patients who have the co-mutated ESR1 and PI3 kinase alterations.

 

Please vote. We are seeing the vast majority of people are voting for benefit irrespective of ESR1 mutation status, which is correct.

 

[01:26:44]

 

Posttest 4: Rationale

 

A key part of the update that we saw from EMBER-3 was that the progression-free survival benefit of the combination of imlunestrant and abemaciclib vs imlunestrant alone was irrespective of ESR1 mutation status. You will see the numbers here. It was irrespective of co-mutation status. This is important, again, because it is teaching us that using a combination co-targeting resistance pathways is superior than monotherapy and may overcome any restriction on the ESR1 mutation.

 

Great job with your voting. Thank you.

 

[01:27:23]

 

Other Studies of Interest

 

Just as a note, here are other studies that we thought were of interest from San Antonio. In the interest of time, I am going to push on, but these are here for your reference and links if you would like to read about them.

 

[01:27:36]

 

Q&A Part 1

 

We had some time set aside for Q&A. Because we have a lot of material to cover in the early stage part, I would suggest if you have additional questions, please submit them through the Q&A button at the bottom of your screen, and we can answer these in real time as we are looking at the next section of slides.

 

Now we are going to turn to the early stage setting. This is Bridging Early Breast Cancer Discoveries to Practice. I am going to turn this over to Virginia.

 

I know you are all excited to hear from Virginia, but before we do that, we are going to just give you a quick quiz.

 

[01:28:22]

 

Pretest 5

 

Let us start. One of the most exciting studies that you are about to hear about is the phase III lidERA trial. This was a trial of adjuvant giredestrant compared with standard of care endocrine therapy in patients with ER-positive early-breast cancer. Which of the following most accurately describes the magnitude of risk reduction of invasive disease recurrence or death based on the primary endpoint of iDFS? Is it:

 

1. 20%;
2. 30%;
3. 40%; or
4. 50%.

 

Please vote. Our answers are across the board, although half the people are voting for 30%. Let us remember that number.

 

[01:29:27]

 

Pretest 6

 

Our final pretest question. Based on the data presented at San Antonio for the phase III DESTINY-Breast11 trial of neoadjuvant T-DXd with or without THP vs dose-dense AC with THP in patients with high-risk, HER2-positive early breast cancer, which of the following correctly describes the adjudicated drug-related ILD pneumonitis outcomes? Here are the answers.

 

1. Overall incidence was similar between arms; grade 3 or more events most common with dose dense AC-THP;
2. Overall incidence was similar between arms; grade 3 or more events were most common with T-DXd-THP;
3. Overall incidence was higher with T-DXd-THP vs AC-THP and grade 3 or more events were less common with AC-THP; or
4. Overall incidence was higher with AC-THP vs T-DXd-THP with grade 3 or more events most common with T-DXd-THP.

 

Give it your best shot. Let us vote. We have votes across the board, the majority looking at grade 3 or more events less common with dose dense AC-THP.

 

Now we will turn it over to Virginia, and we are going to jump right into the monarchE study.

 

monarchE Subgroup Analysis by Nodal Status: Adj Abemaciclib + ET for High-Risk, Node-Positive, HR+/HER2- EBC

 

Dr Virginia Kaklamani (MD Anderson Cancer Center): Thanks, Erica. 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.

 

[01:31:45]

 

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 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 nice benefit with the addition of abemaciclib here.

 

[01:32:42]

 

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?

 

[01:33:51]

 

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 nice benefit with giving ribociclib for 3 years.

 

[01:34:08]

 

NATALEE: Absolute DDFS Benefit by Anatomical Stage

 

Then when looking at the different stages of disease, as you can see here, 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.

 

[01:34:45]

 

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?

 

As you can see here, the patients that had distant metastatic disease, most of them developed metastatic disease to the bones, although liver was next. As you can see again, 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.

 

[01:35:52]

 

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 this year's 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 with all your typical secondary endpoints.

 

[01:37:20]

 

lidERA: Baseline Characteristics

 

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?

 

[01:37:57]

 

lidERA: IDFS (Primary Endpoint)

 

These are the results. As you can see, 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. So early results, but still positive favoring the use of giredestrant.

 

[01:38:29]

 

lidERA: IDFS by Subgroup

 

Now when looking at subset of patients, again, 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.

 

[01:38:57]

 

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.

 

[01:39:30]

 

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 as you can see here.

 

Most importantly, when looking at treatment discontinuation, 5% in the giredestrant arm compared to 8% in the standard of care endocrine therapy arm.

 

[01:40:05]

 

lidERA: Safety (cont’d)

 

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.

 

[01:40:49]

 

SOLTI-2104-PremiÈRe: Elacestrant ± Triptorelin in Premenopausal Women With ER-Positive/HER2-Negative EBC

 

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.

 

[01:42:10]

 

SOLTI-2104-PremiÈRe: CCCA Rate, Ki67 Change, ER/PgR Level Change

 

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, you can see that 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.

 

[01:43:06]

 

SOLTI-2104-PremiÈRe: Change in Ki67 Levels from Baseline and by PAM50 Intrinsic Subtype

 

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?

 

As you can see here from this slide, the first part of the slide is showing us the elacestrant-only arm. The second part is showing us elacestrant plus triptorelin. 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. That is again showing us some good activity.

 

[01:43:50]

 

SOLTI-2104-PremiÈRe: Other Study Outcomes

 

Some other outcomes that they looked at. 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.

 

[01:44:11]

 

DESTINY-Breast11: Safety Analysis of Neoadjuvant T-DXd With or Without THP vs ddAC-THP in Patients with High-Risk HER2+ EBC

 

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.

 

[01:45:35]

 

DESTINY-Breast11: pCR in Each Arm (Primary Endpoint)

 

When looking at the results that were presented at ESMO, as you can see, 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 AC-THP therapy.

 

[01:46:19]

 

DESTINY-Breast11: Adjudicated Drug-Related ILD/Pneumonitis Events by Cycle

 

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 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.

 

[01:47:32]

 

DESTINY-Breast11: Adjudicated Drug-Related ILD/Pneumonitis Serious AEs, Discontinuations, and Dosing Alterations

 

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.

 

[01:47:53]

 

DESTINY-Breast11: Adjudicated Drug-Related ILD/Pneumonitis Steroid Use and Outcome

 

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.

 

[01:48:19]

 

DESTINY-Breast11: Other AEs and Management

 

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, as you can imagine.

 

[01:49:31]

 

PHERGuide: Translational Evaluation Substudy of ctDNA in Patients With HER2+ EBC From PHERGain

 

This takes us to another interesting trial, the PHERGain trial. The PHERGain trial has been presented a few times in the past and looked at a very interesting approach of not giving cytotoxic therapy to every single patient that has early stage HER2-positive disease.

 

On this clinical trial, some of the patients received TCHP chemotherapy as standard of care, but some of them started with HP. After receiving HP, there was an assessment of tumor response. Patients that had tumor response could have continued receiving HP and patients that did not were switched to TCHP.

 

This approach seemed to produce nice rates of PCR in patients and seem to be something that we should be at least studying more in the future to be able to de-escalate therapy for some of our patients that are having good response to non-chemotherapy-based regimen.

 

Now the presentation here was a sub-study of the PHERGain called the PHERGuide study. This is a study looking at ctDNA.

 

[01:50:53]

 

PHERGuide: Correlation Between ctDNA at Baseline and Disease Stage, Nodal Status, and pCR

 

What they were able to show with this study because as you can imagine, they collected ctDNA at several time points. This is just a correlation between outcomes and ctDNA. First of all, the likelihood of finding ctDNA was pretty high. Even in stage I breast cancer patients, 33% had positive ctDNA.

 

Once that stage increased to II and III, that rate increased to 71% and 93%. And similar outcomes with the nodal status, node-positive patients had an 87.8% rate of positivity in the ctDNA, compared to 55% in the node-negative patients.

 

Now, there did not seem to be any correlation between the ctDNA that was found at baseline and the PCR status, which is important. But ctDNA was predictive of long-term outcomes.

 

[01:51:43]

 

PHERGuide: ctDNA Dynamics and pCR

 

Here we can look at the ctDNA dynamics and PCR. As you can see here, the majority of patients that had ctDNA positivity ended up at cycle 3 converting into ctDNA negativity. The patients that had ctDNA negativity, most of them remained ctDNA negative at the cycle 3 day 1 treatment.

 

The patients that did not have any ctDNA clearance had a lower rate of response, and the response was measured by PET scan compared to the patients that had ctDNA clearance. ctDNA was predictive of response to therapy, which is something that we have seen in other studies as well.

 

[01:52:36]

 

PHERGuide: 3-Yr iDFS and ctDNA Status Over Time

 

Then when looking at the 3-year invasive disease-free survival, depending on ctDNA status, as you can imagine, the patients that had a positive ctDNA at baseline had a worse 3-year invasive disease-free survival rate compared to the patients that had a negative ctDNA.

 

Again, prognostic ctDNA, which is something that we have seen in many other studies. What we really need to be looking at is can it help us stratify patients into different lines of therapy? This is something that we are currently missing.

 

[01:53:20]

 

PHERGuide: 3-Yr iDFS and ctDNA Dynamics

 

Again, looking at early vs late ctDNA dynamics, similar picture here with patients that did not have any ctDNA at baseline having 100% survival at 3 years compared to patients that had some ctDNA, especially the ones that did not clear their ctDNA.

 

[01:53:46]

 

ALTTO ET Analysis: Adjuvant AI or Tamoxifen in HR+/HER2+ EBC

 

Another study that is an old study. We probably forgot about it, but it reemerged because it looked at the type of endocrine therapy that we should be giving in patients that have triple-positive breast cancer is the ALTTO trial.

 

The ALTTO trial looked at incorporating lapatinib to the early-stage therapy of HER2-positive breast cancer patients. Several arms to the trial that included trastuzumab lapatinib, trastuzumab followed by lapatinib, combination of trastuzumab and lapatinib.

 

This presentation was really looking at the use of ovarian suppression, as well as an aromatase inhibitor vs tamoxifen in this early-stage breast cancer patient population. We really do not have a lot of data.

 

[01:54:34]

 

ALTTO ET Analysis: DFS, TTDR, OS in All Patients

 

When we look at the SOFT and the TEXT trial, most of those patients had HER2-negative disease. So, we do not have a lot of data on whether we should be giving an aromatase inhibitor or a SERM, ovarian function suppression and so forth in these HER2-positive breast cancer patients.

 

The data from the ALTTO trial showed that the aromatase inhibitor was superior to tamoxifen, which we have seen in the non-HER2 positive subset as well. Looking at 10-year disease-free survival, 80.1% with the AI, compared to 76.5% with tamoxifen and same trend with overall survival as well.

 

In premenopausal patients, similar outcomes; postmenopausal patients similar outcomes, suggesting that giving an aromatase inhibitor is going to benefit our patients more than giving a SERM.

 

[01:55:30]

 

ALTTO ET Analysis: Type of First DFS Event

 

When looking at types of recurrences and whether there is again a benefit of the AI vs the SERM, same picture here. There is fewer local recurrences with the AI, fewer distant recurrences as well with the aromatase inhibitor compared to tamoxifen.

 

As far as site of metastatic disease, there did not seem to be a huge difference between the arms. But again, fewer recurrences in general with the use of the AI compared to the SERM.

 

[01:56:03]

 

ALTTO ET Analysis: DFS, TTDR, OS in Premenopausal Patients

 

As far as whether we should be giving an aromatase inhibitor, an OFS vs a SERM, the results were very similar to what we have seen with TEXT and SOFT, suggesting that ovarian function suppression will benefit our patients more than not giving OFS. You can see the 10-year disease-free survival at 90% with an AI plus/minus OFS vs a SERM at 77.6%. There did not seem to be a big difference if you added ovarian suppression to the SERM.

 

I will pass this on to Erica to finish us up with the triple-negative early-stage breast cancer.

 

[01:56:36]

 

CITRINE: Adjuvant Carboplatin Intensified Chemotherapy vs SoC Chemotherapy in Patients With High-Risk Early TNBC

 

Dr Mayer: Thank you so much, Virginia. What a fabulous summary. Hang on, everyone. We are in the homestretch, and we just have a few more abstracts to get through.

 

A very interesting abstract that was presented was the CITRINE study, which was adjuvant carboplatin intensified chemotherapy vs standard of care chemotherapy for high-risk early triple-negative breast cancer.

 

This was a large study, 800 patients exclusively conducted in China. It was asking the question, does the addition of carboplatin to our standard anthracycline and taxane-based regimen add? This has been a point of debate over the past decade, with many studies and meta-analyses in both the preoperative and adjuvant settings trying to answer this question.

 

However, in the era of KEYNOTE-522, where the majority of us are providing therapy in the preoperative setting with pembrolizumab, this has been a little bit less of an active question. However, this is well done phase III trial that is designed to help answer.

 

This trial enrolled patients with either node-positive or node-negative, triple-negative breast cancer and randomized to a regimen of dose-dense epirubicin cyclophosphamide and then followed by paclitaxel with the addition of weekly carboplatin AUC2 vs a standard regimen of epirubicin, cyclophosphamide and paclitaxel with a primary endpoint of progression-free survival or disease-free survival.

 

[01:58:19]

 

CITRINE: DFS (Primary Endpoint)

 

Here is the primary endpoint at a median follow-up of 44.7 months. The patients who had the addition of carboplatin to their backbone chemotherapy regimen had a significant improvement in their disease-free survival, an improvement of about 7%, with a hazard ratio 0.64.

 

Interestingly, the benefit from this regimen occurred quite early on in the first year. The curves began to separate. Between 1 to 3 years, the curves stabilize and then remain parallel. So, it is showing us that it is helping particularly for those early recurrences to add in the fourth chemotherapy.

 

Recurrence-free survival, disease-free survival and overall survival showed similar trends in numeric benefit with the intensified chemotherapy.

 

Now, what is the cost of doing this of adding the fourth chemo?

 

[01:59:15]

 

CITRINE: Safety Summary

 

Let us look at safety. We do see that the incidence of grade 3/4 treatment-related adverse events was higher in the carboplatin arm vs the standard of care, 66.7% vs 55%. So a higher number, although I would say not dramatically higher. In general, when you look at this tornado plot, it looks reasonably balanced between the arms.

 

Additionally, discontinuation due to toxicity was actually less common in the intensified arm 22% vs patients in the standard of care arm, which was 26%.

 

Now, there was a second study presented at San Antonio as well, also from China, similarly looking at the addition of adjuvant carboplatin to an anthracycline and taxane-based regimen also showing similar benefits in terms of improvement in disease-free survival. As discussed by Priyanka Sharma, who discussed these abstracts, this probably answers the question that if one is giving adjuvant anthracycline and taxane-based chemotherapy for triple-negative breast cancer, it is very reasonable to consider the addition of carboplatin.

 

However, the relevance of this data, particularly for providers in countries with access to KEYNOTE-522, is of less value as the majority of our patients who are presenting with certainly stage II or III triple-negative breast cancer are receiving the ACTC plus pembrolizumab regimen in the preoperative setting, and so would not be candidates for this type of adjuvant approach.

 

In a country that does not have easy access to preoperative pembrolizumab, this would be very reasonable to consider. Once in a while in our clinics, we do have patients who do not receive preoperative therapy and end up having a significant disease at the time of surgery and we are giving adjuvant chemo, and this again would be appropriate.

 

It also raises the question, can we move away from anthracycline for triple-negative breast cancer? This study was not designed to ask this, but that is an important question that is being looked at in a variety of other studies that can include carboplatin and taxane as backbone treatment.

 

[02:01:23]

 

Studies of Neoadjuvant PARPi + PD-1/PD-L1 Inhibitors in EBC

 

Next, we have 2 abstracts on one slide because they are actually quite similar. These are studies that are looking at preoperative therapy for patients who have triple-negative breast cancer and BRCA 1/2 gene mutations. These are patients for whom we are often using PARP inhibitors at different points in time in their treatment.

 

These studies one is called TBCRC-056. The other is called OlympiaN. We are looking at the activity of preoperative PARP inhibitor for patients presenting with BRCA-associated triple-negative breast cancer.

 

Now, there have been some previous efforts in this space looking at giving up to 6 months of monotherapy with PARP inhibitor showing a pathologic complete response rate that approaches 50%. These studies were actually both designed to look not only at PARP inhibitor, but also at the addition of a PD-1 or PD-L1 inhibitor in the early stage setting.

 

Let us go through each trial.

 

First, let us look at TBCRC-056. This was a study for patients with stage I to III triple-negative breast cancer. I will point out 37% stage I, 46% stage II, 17% stage III. About a quarter had node-positive disease. There were actually 46 patients enrolled in the study. Patients received 18 weeks of PARP inhibitor using niraparib and a PD-1 inhibitor, dostarlimab, with dual primary endpoints of pathologic complete response and recruitment of stromal TILs from baseline.

 

The study showed a pathologic complete response rate of 50% and an RCB 0/1 rate of 60%. So it showed a high level of activity, including in the patients with node-positive disease and patients with stage III disease.

 

Additionally, the study demonstrated that in both arms of the study, one arm had a lead in of PARP inhibitor monotherapy, showed a significant increase in recruitment in stromal TILs, so met both primary endpoints.

 

In general, the toxicities experienced were classic for these types of medications, including PARP inhibitor and immunotherapy. But the vast majority of patients were able to complete their treatment, and about 13% had to stop for either toxicity or for disease progression.

 

Now let us look at OlympiaN. This was a slightly different study. It had 2 cohorts. Cohort A was what I would call very low risk and cohort B was low risk. Both of these cohorts enrolled patients with triple-negative breast cancer and BRCA gene mutation. Cohort A was designed to be treatment with olaparib monotherapy for up to 6 months. Then cohort B was designed to give olaparib with durvalumab.

 

Now, in essence, the patients who actually were enrolled in OlympiaN were all node-negative and they were all T1B or T1C. So it is a lower risk population than the TBCRC-056. But the PCR rates were very robust, 70% in cohort A, 80% in cohort B. Again, the toxicities observed were consistent with the agents that were being used.

 

Overall, this data is really exciting, suggesting that for this distinct population of patients with pathogenic gene mutations, that there may be an option to provide a nonchemotherapy approach, particularly built around use of prolonged PARP inhibitor in the setting, achieving pathologic complete response rates that are not that dissimilar than what we see with giving KEYNOTE-522.

 

A question these studies are not able to answer is, what is the contribution of the immunotherapy agent in this setting? Both studies will have extensive correlative analysis which we will try to dissect out. What is the PD-1/PD-L1 inhibitor contributing? Also can we identify who are the patients who are getting this marvelous response, who might be candidates for this in the future?

 

[02:05:45]

 

Posttest 5

 

That brings us to the end of the review of the early stage abstracts. Now we are going to return to our questions, which I am sure you are going to ace.

 

Our first question, let us return back to the phase III lidERA trial of adjuvant giredestrant compared to standard of care endocrine therapy in patients with ER-positive/HER2-negative early breast cancer. Which of the following most accurately describes the magnitude of risk reduction of invasive disease recurrence or death based on the primary endpoint of IDFS in this trial?

 

1. 20%;
2. 30%;
3. 40%; or
4. 50%.

 

Please vote. People did very well.

 

[02:06:43]

 

Posttest 5: Rationale

 

The correct answer is 30% because this corresponds to the hazard ratio of 0.7. We had 80% of people who voted, and that is better than we did the first time around. Just as a reminder, again, the iDFS benefit had a hazard ratio of 0.7, which was maintained at both 12 months, 24 months and 36 months in the lidERA study. Additionally, the exploratory analysis showed that the benefit from giredestrant was consistent whether the comparator was aromatase inhibitor or tamoxifen.

 

[02:07:20]

 

Posttest 6

 

Great job. We have our final question. Based on the data presented at San Antonio for the phase III DESTINY-Breast11 trial of neoadjuvant T-DXd, with or without THP vs AC-THP in patients with high-risk HER2-positive early breast cancer, which of the following correctly describes the adjudicated drug-related ILD/pneumonitis outcomes? Is it that:

 

1. The incidence was similar between arms, but grade 3 events were most common in the AC arm;
2. The incidence was similar between arms, but grade 3 events were most common in the T-DXd-THP arm;
3. Incidence was higher with T-DXd-THP vs AC, but grade 3 events were less common with AC; or
4. Incidence was higher with AC-THP vs T-DXd-THP with grade 3 or more events most common with T-DXd-THP.

 

I know that is complex. Let us do your best with that.

 

[02:08:40]

 

Posttest 6: Rationale

 

This is a complex question. I recognize this. But as you heard from Virginia, the overall incidence of ILD/pneumonitis was similar between arms. Interestingly, the grade 3 or more events were actually most common with dose-dense AC-THP. The rate of ILD/pneumonitis was fairly low, 4.4% vs 5.1% vs 4.9%, but the higher rates of adjudicated ILD/pneumonitis were most common with the AC-THP. So, another piece of data that supports the benefit of the T-DXd-THP regimen in this setting.

 

[02:09:27]

 

Other Studies of Interest

 

I just want to point out a couple other studies which really were important and interesting. One of them is TBCRC-053, also known as the P-RAD study. This was a study that was looking at giving essentially the KEYNOTE-522 regimen to patients with node-positive hormone receptor-positive/HER2-negative breast cancer with different doses of radiation, trying to achieve the abscopal effect, trying to stimulate the immune system and help the immunotherapy work better.

 

The study was built around looking at recruitment of T cells, and definitely demonstrated that providing radiation to the breast led to recruitment of T cells in the setting of this treatment, and actually did show some robust PCR rates, something that I hope we will be able to study further, and wonderful correlative science that accompanied that trial.

 

We also saw an update from DESTINY-Breast05, which is, in some ways, a partner study of DESTINY-Breast11 that evaluated patients with high-risk HER2-positive breast cancer who had residual disease after neoadjuvant treatment, randomized to T-DXd vs T-DM1.

 

We had seen this data presented at ESMO showing the superiority of T-DXd in this setting over T-DM1. Importantly, in this update, it was looking at toxicity and showed us that whether patients were receiving sequential radiation with their HER2-based therapy or giving the radiation in parallel at the same time, there was no increase in rates of interstitial lung disease. I know that is a question that many of us have in clinic as we consider this data and consider how we might operationalize it in our clinical setting.

 

[02:11:12]

 

Q&A Part 2

 

We have just a couple minutes left, and we have time for any questions. Many of our questions have already been answered. We have some final polls that we are going to do. But before we get to these, 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 the 2 of you 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 Mayer: Great question. As Sara has been a discussant of this data, maybe I will turn to Sara for her take on this first.

 

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 US, 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.

 

Dr Mayer: I agree completely with everything that Sara has said, and I also feel like, we as a breast cancer community, need to support doing this kind of trial so we can take what has become one of the most powerful and exciting therapies that we have seen in a decade in breast cancer and figure out who should we be giving it to, for how long, how many cycles, and how can we bring the whole spectrum of heterogeneous disease to cure as best we can?

 

I hope we can have some trial designs that will allow us to be able to tailor therapy appropriately.