Dr Kaklamani: Let us start with adjuvant endocrine therapy. This is a field that has had quite a few changes in the past several years.

[00:04:08]

2022 ASCO Guidelines: Biomarkers for Adjuvant ET and CT for HR+/HER2- EBC

The first question is, obviously, how do we select patients for chemotherapy versus not? This is where we get help from several genomic assays. This is the most recent update from ASCO looking at the different genomic assays that we use in the adjuvant setting.

As you can see, there is differences between pre and postmenopausal patients. In premenopausal patients that have node-negative disease, we like using Oncotype DX. In node-positive patients, we really at this point consider chemotherapy as a standard of care option, although a lot of us feel that the ovarian suppressive properties of chemotherapy is really what works. There is current investigations into that.

Then for our postmenopausal patients that have node-negative disease, again, we can use Oncotype DX, although other assays can be used as well. For node-positive patients, we have results from the RxPONDER trial that again point toward the use of Oncotype DX in helping select patients that would benefit from chemotherapy or not.

Now if patients have 4 or more positive lymph nodes, the standard of care is chemotherapy without doing any genomic assay. This is pretty standard. I think most of us agree with this schema, and it really helps put everything into perspective and helps select the right patients for chemotherapy or for remission of chemotherapy.

[00:05:29]

Patient Case 1: Woman With Grade 2 IDC and 1 Positive Node

Let us start with a case. This is a 42-year-old premenopausal patient. She has grade 2 IDC, status post lumpectomy and sentinel biopsy. She is found to have a 3.2 centimeter tumor. It is grade 2. ER+, PR+, and then HER2 1+ and her FISH is negative. Her Ki-67 is 35, so increased.

She has 1 out of 3 positive lymph nodes, but those are with ITCs. It is really N0i+. Her BRCA status is negative. Based on all of these findings, she has given ACT for 6 cycles, radiation therapy, and then starting endocrine therapy.

[00:06:13]

Pretest 1

The question here in this patient is do we give:

1. Endocrine therapy by itself;
2. Ovarian suppression, endocrine therapy and abemaciclib; or
3. Ribociclib; or
4. OFS, tamoxifen and then abemaciclib; or
5. Ribociclib.

Most people want to use a CDK4/6 inhibitor, abemaciclib or ribociclib, but we will go over the data as well. Some people are also favoring tamoxifen and we can talk about that option too.

[00:07:25]

Risk Assessment Algorithm to Inform Systemic Adjuvant Therapy Selection in EBC

Let us take a look. How do we assess this patient? Patient has T2 disease. She has a high risk of recurrence based on her Ki-67. How do we think of giving endocrine therapy? How do we think of giving ovarian suppression?

This is a premenopausal patient. She is a candidate for chemotherapy. Many of the guidelines are recommending that we give also ovarian suppression to this patient. But one of the questions is going to be probably some CDK4/6 inhibitor without increased Ki-67 is needed.

Now abemaciclib is not approved in patients that have node-negative disease based on the data from monarchE. We will go over that data. Ribociclib is, because this is a high-risk stage II breast cancer.

[00:08:25]

monarchE and NATALEE Trial Populations

These are the criteria of inclusion between the NATALEE trial using adjuvant ribociclib and the monarchE trial using adjuvant abemaciclib. You can see that stage I disease is not included unless patients have a micrometastatic disease. Then there are some patients that were included in the monarchE trial as long as they had high Ki-67 or grade 3 disease.

But the majority of patients that we are going to be looking at are either those T2N0s, where only ribociclib was looked at, or other patients that have higher risk disease where we can use either ribociclib or abemaciclib.

The differences are the ribociclib is given for 3 years, abemaciclib is given for 2 years, and the ribociclib dose is lower than that in the metastatic setting. Toxicity-wise, it probably is a little bit more favorable compared to the abemaciclib dose.

[00:09:22]

monarchE: 5-Yr iDFS in ITT Population

Here is the data from monarchE, which is the most mature of the 2 trials, 5-year invasive disease-free survival in the intention-to-treat population. You can see a nice difference with an absolute difference of 7.6% favoring the group that received abemaciclib.

We are basing our approval on this data. We are basing on the use of adjuvant CDK4/6 inhibitor on this pretty mature 5-year data.

[00:09:48]

NATALEE: 4-Yr iDFS in ITT Population

Now, NATALEE is lagging behind by a year or so. This is the 4-year iDFS, but very similar in trend as well as really absolute values compared to the monarchE trial.

Here, the patient population was a little bit lower risk. That is why we are seeing the differences because N0 patients were included. But the absolute difference you can see in that 4-year is 4.9%.

[00:10:17]

NATALEE: iDFS by Nodal Status

Nodal status. There is a lot of debate as to whether we should be giving a CDK4/6 inhibitor in patients that have node-negative disease. You can see here the difference between node-negative and node-positive, very similar. We are still talking about higher risk node-negative patients. Their outcomes may be a little bit better than we see with N1 to 3 disease, but still absolute difference of 5% with the addition of ribociclib. I personally look at that criteria and base my use of ribociclib on the NATALEE criteria.

[00:10:53]

monarchE: ctDNA Dynamics and iDFS Outcome

Now, something that was pretty interesting, and again it is hard to interpret and hard to put into standard of care yet. But they looked at ctDNA dynamics in monarchE and they had patients that had persistently negative ctDNA dynamics and those patients did the best. Had patients that initially were positive but then became negative and those patients did second best.

Then they had patients that became positive after being negative in that red curve. You see that unfortunately their outcomes were not very good. Patients that started out as being positive and then continued being positive and they had the worst outcomes.

The bottom line is that ctDNA does help and it is a great prognostic marker. The question is, is it a predictive marker? We do not have that data yet, but this is the first data set that has looked at this in a prospective way in the adjuvant setting. We are going to have more, and now we are designing trials looking at that ctDNA to try to change therapies to see if we can salvage some patients.

[00:12:00]

Patient Case 1: Woman With Grade 2 IDC and 1 Positive Node

Going back to that patient, 42-year-old, premenopausal, 3.2 centimeter, grade 2 IDC. ER/PR+, HER2-negative, 1 lymph node with ITCs. She received chemotherapy. She had a Ki-67 of 35%.

[00:12:20]

Posttest 1

The question again is, what do we give her as endocrine therapy? Do we give:

1. Just endocrine therapy by itself;
2. Ovarian suppression, AI and abemaciclib;
3. Ovarian suppression, nonsteroidal AI and ribociclib;
4. Tamoxifen with OFS and abemaciclib; or
5. Tamoxifen with OFS and ribociclib.

Here we are seeing more abemaciclib and ribociclib compared to the initial. Tamoxifen has a couple of issues. First of all, we do not want to combine it with ribociclib because of the QTc prolongation. That is something to keep in mind.

Secondly, when you are combining tamoxifen and abemaciclib, you are increasing the risk of thromboembolic events, which is one of the adverse events with abemaciclib as well. I personally do not use Tamoxifen. I do not know Dr Abraham, if you use tamoxifen in combination with the CDK here or if you go to an aromatase inhibitor?

Dr Jame Abraham (Cleveland Clinic): I will go with an AI, as you mentioned in SOFT and TEXT trial in a premenopausal woman who received chemo. That is the patient who will benefit from ovarian suppression. I fully agree with you.

[00:14:03]

Posttest 1: Rationale

Dr Kaklamani: Perfect. Thank you. Okay. Because again, this is a node-negative patient, the ITCs are considered node-negative. That is why we want to give ribociclib. Abemaciclib was not looked at in node-negative patients, just in node-positive. The consideration here is ribociclib based on the results from the NATALEE trial.

[00:14:28]

Panel Discussion: HR+/HER2- EBC

Here is a few things to keep in mind. First of all, when do we recommend use of a CDK4/6 inhibitor? I will ask Dr Abraham as well. I typically tend to look at the 2 clinical trials and I use the inclusion criteria of those trials. But is there a patient that you would potentially maybe diverge from a trial, let us say, actually a patient I just saw in clinic had a 1.8 centimeter tumor, grade 3, high Ki-67. We did an Oncotype and it was 35. She received chemotherapy. Would that be a patient, for example, that you would want to give an adjuvant CDK4/6 inhibitor to?

Dr Abraham: That is a good question. Let us just say she is 32 or 29. Then, of course, you are worried about the long-term risk, what is going to happen 30 years from now, 40 years from now. But unfortunately that patient is not included in the clinical trial, so I will have tough time convincing any insurance to pay.

I will give you an example. Today, we discussed a patient in the tumor board. She is 41, 2.1 centimeter tumor, node-negative. The Oncotype recurrence score was 30, and grade 3. That is one patient we do not usually think about CDK4/6, but of course she fits the criteria, as you mentioned, the NATALEE trial. We will recommend ribociclib for her.

Dr Kaklamani: Yes. I agree with you. I think a lot of times we want to try to extrapolate and potentially include patients that were not on those trials, but at some point you have to draw the line somewhere and I try to draw it where we have the data. That is what I do as well.

Then as far as adverse events, there is things to keep in mind. The adverse event profile of abemaciclib and ribociclib are a little bit different. With ribociclib, you will have more cytopenias, a little bit higher risk of infections, but at the same time it is much better tolerated than in the metastatic setting because it is a lower dose. Abemaciclib is going to have some diarrhea. There is people that dose escalate abemaciclib, and there is an active trial that is being conducted looking at dose escalation every 2 weeks, starting at 50 BID, a 100 BID, and then 150.

We will see what the results show. I am assuming it is going to be better tolerated. I think that month and a half of getting to the full dose should not really impact efficacy. But in the meantime, we talk to our patients about antidiarrheals.

The other thing to keep in mind is a small but definitely increased risk of ILD, and as I mentioned, venous thromboembolic events as well.

Then I guess Dr Abraham, I will ask your opinion about the ctDNA monitoring. Do you do that in your practice? I am sure patients come and ask all the time.

Dr Abraham: Patients come and ask all the time and they have a printout and the friend and neighbor said, this is the most important thing you can do. I mean, if somebody really wants to do, and I will say, okay, sure. But of course, as you know really well, none of the guidelines recommend that and we do not use that routinely. But if the patient insists, then I will do it.

Now, I do not know what you do? How do you do it?

Dr Kaklamani: I try to discourage them as much as I can from getting it done because I do not know what to do with the results. I remember one of my colleagues who thinks similarly to me, a patient convinced her to get that assay done and it was positive. She got scans and the scans were negative. Then she sent a text to our group and said, so what do I do? My response was good luck.

Dr Abraham: I know.

Dr Kaklamani: Because we do not know what to do. I think this is what we need to explain to patients that until we have predictive value of these tests, it is really hard to make decisions based on them. Then you just have somebody that is living knowing that their ctDNA is positive, and as you saw from these outcomes, they are pretty bad. I personally try very, very hard to discourage them.

Dr Abraham: Yeah, that is tough. You are right.

[00:18:44]

Advanced-Stage Breast Cancer: Current Biomarker Testing and Treatment

Dr Kaklamani: Okay. Now we are going to go into the advanced setting. I will let Dr Abraham take over.

Dr Abraham: Okay. Thank you, Dr Kaklamani. I am going to talk about advanced breast cancer and we will start with a pretest question.

[00:19:00]

Pretest 1

In your current practice, how often do you test your patients with HR+/HER2- metastatic breast cancer for ESR1, PIK3, AKT, and PTEN genomic alterations. The answers are:

1. Never;
2. Rarely;
3. Sometimes;
4. Often;
5. Always.

Okay, 33% said never and then 13% said always. Okay, we can come back and review this.

[00:19:47]

HER2 IHC Testing Today

This is a really interesting slide. I am sure, let us just say 10 or 15 years back or even longer than that, we used to look at these slides closely when the HER2-targeted agents were coming to the metastatic and adjuvant setting.

Of course, IHC 3+, there is no debate on that. IHC 2+, that is where we do in situ hybridization for ratio more than 2, that is positive, less than 2, that is negative. Then we can help equivocal if the copy numbers are high and the ratio is low.

Score 1+, of course, that is HER2- but in the new category of HER2-low. Then of course, HER2 2+ with FISH-negative is considered as HER2-low.

Looking at IHC 0, that is the next nuance of the conversation. Let us just say there is absolutely no staining, then it is clearly a HER2 null. But if the HER2 receptor is, let us just say ultralow, that is the new category, subset of HER2- negative breast cancer or HER2 protein expression is even lower than the HER2-low breast cancer. It is characterized by a faint or incomplete membrane staining in less than 10% of tumor cells.

I think this is something we need to continue to educate ourselves, continue to educate our team and educate our pathologists why this is important based upon some of the newer FDA approval for trastuzumab deruxtecan.

If you look at the percentage, about 35% of the patients have HER2-low. Again, in those patients, we can use trastuzumab deruxtecan. Then in patients with ultralow, again, we can use T-DXd based upon DESTINY-Breast06 data.

That gives a fairly broader indication for T-DXd in metastatic breast cancer. That is really exciting news for our patients.

[00:22:21]

ESR1 and PIK3CA Pathway Biomarker Testing Recommendations

Moving on to ESR1 and PIK3. Both can be tested using ctDNA or tissue. ASCO recommends using ctDNA for ESR1 due to higher sensitivity. Both can be done with NGS or PCR.

ESR1, the difference is it is an acquired mutation. It happens while the patient is exposed or after the patient is exposed to an endocrine treatment, especially aromatase inhibitor. Usually the recommendation is to consider doing an NGS testing when the patient progress on an endocrine treatment.

Because of the availability of ctDNA and it is a blood test, and so it is easy for us to do NGS multiple time points and we do not have to do a repeat biopsy. That is what I usually do.

Then PIK3 mutations that typically develop early and are present in both primary and metastatic tumor samples. Again, the importance of this is, of course, prognosis and treatment selection.

[00:23:42]

Current Treatment Considerations for HR+/HER2- MBC

This is something we published about 6 months back looking at HR+/HER2- metastatic breast cancer. If the recurrence happened more than 12 months after completing adjuvant AI or no previous exposure means de novo or no previous exposure to AI when a patient treated with tamoxifen, then the first-line treatment is non-steroid AI plus CDK4/6 inhibitor.

You can pick your choice of CDK4/6 from ribociclib to abemaciclib to palbociclib depending upon the comorbid conditions of the patient and your listing of an overall survival.

If the recurrence while on adjuvant AI or less than 12 months since the completion of AI, then fulvestrant plus CDK4/6. If the disease progress, then do genomic profiling, select treatment based upon ESR1 mutation, PIK3 AKT. Then there are a number of options based upon the genetic testing there.

As I said, we published this in August or so and October November or I think December at San Antonio that INAVO data was presented. Even this schema became outdated.

Now potentially we can consider NGS testing in first-line, especially in patients who recurred while on adjuvant AI or less than 12 months on AI, and then consider inavolisib plus palbociclib plus fulvestrant in those patients.

[00:25:40]

Guidelines for Biomarker Testing and Targeted Therapies in Breast Cancer

This is a different way of looking at the same data. This is from the NCCN. PIK3, as I said, we have inavolisib, palbociclib, fulvestrant data. Then if the patient has PIK3 or AKT1 activating or PTEN, then capivasertib is available with fulvestrant, ESR1, of course, elacestrant.

If the patient has germline mutation, olaparib, talazoparib. I have not used some of the NTRK fusion agents. MSI-high, you can use pembrolizumab. Tumor mutation burden-high, again, pembrolizumab. I have not used an RET inhibitor yet.

[00:26:28]

Current Treatment Considerations for HR+/HER2- MBC

This is in patients with endocrine refractory or visceral crisis. If the patient has a HER2-low, IHC 1+. Again, this slide is outdated. Now I need to say that if the patient has IHC 0 and ultralow, that can be considered for T-DXd.

Then even this particular point is actually outdated again. NCCN, we recently changed this one to first-line. Even without the patient getting chemotherapy, they can have T-DXd based upon DESTINY-Breast06.

Then if the patient had chemo exposure, patient is not a candidate for T-DXd, sacituzumab govitecan. Then, of course, if the patient has germline mutation, olaparib or talazoparib. Then of course if the patient has none of these options, we can consider chemotherapy with capecitabine.

Again, this depends on patient's preference, patient's comorbid conditions. There is nothing wrong in bringing capecitabine early on if that is their patient's preference.

[00:27:43]

Posttest 2

Okay, now let us just do the post test. We are asking the same question. How often do you plan to test your patients with HR+/HER2- metastatic breast cancer for ESR1, PIK3, AKT and PTEN genomic alterations? We just listened to a number of agents based upon these testing and we just learned that ESR1 is an acquired mutation that changes when the patient is exposed to an aromatase inhibitor.

1. Never;
2. Rarely;
3. Sometimes;
4. Often;
5. Always.

Okay, that number again, before never was 44%, now it went down to 9%. I think getting the point across. Often and always is majority. Very good. Thank you.

[00:29:01]

Posttest 2: Rationale  

Again, we are repeating the same thing. In HR+ patients, if you do the testing, potentially we can identify patients for some of the targeted agents for ESR1, PIK3CA, AKT, and PTEN. It is really important for us to repeat the testing and keep an eye for options based upon genomic testing.

That will really allow us to continue to extend our endocrine option for a patient with ER+/HER2- metastatic breast cancer.

[00:29:48]

Patient Case 2: Newly Diagnosed Metastatic BC

Okay, so let us look at this patient. She is 56, post-menopausal. She is presenting de novo metastatic disease to liver and bones. It is again small percentage of patients, probably 5% or 5% to 10% in the US. Strongly ER+, 60%; PR, 40%; HER2 1+.

She was started with an aromatase inhibitor. She is postmenopausal and AI ribociclib based upon the overall survival data. After 6 months, she has decease progression with increase in size and number of liver metastasis. Looks like a genomic testing was done and it did not show any actionable mutation.

[00:30:42]

Poll 3

Which of the following would you recommend for this patient?

1. Abemaciclib plus fulvestrant;
2. Capecitabine as a chemo agent;
3. Exemestane plus everolimus; and
4. T-DXd.

There is no absolute black and white answer here.

Okay. Abemaciclib/fulvestrant, that is about 24%. 20% selected chemo. Almost 30% selected T-DXd, and 30% selected exemestane/everolimus. Okay, let us look at some data.

[00:31:35]

postMONARCH: Fulvestrant ± Abemaciclib Following Progression on Endocrine Therapy + CDK4/6 Inhibitor

This is the postMONARCH, that is fulvestrant plus or minus abemaciclib after progression on endocrine therapy with a CDK4/6 inhibitor. It is double-blind, placebo-controlled, phase III trial, nearly 400 patients. Patients who are exposed to CDK4/6 agents as first-line for metastatic breast cancer.

Abemaciclib/fulvestrant versus placebo plus fulvestrant. The primary endpoint was progression-free survival.

[00:32:18]

postMONARCH: PFS

In this trial, investigator-assessed PFS, there was an improvement when the patients were treated with abemaciclib plus fulvestrant. A 27% and 45% PFS-related event risk reduction with abemaciclib plus fulvestrant.

Let me just see what is the next slide. I think it is very reasonable in a patient who was exposed to CDK4/6 inhibitor, like what we discussed to switch to fulvestrant plus abemaciclib, but again she has been on an endocrine treatment only for 6 months. You can make your on call depending upon the patient's symptoms, liver function tests, means T-DXd or other agents are not completely wrong like capecitabine.

[00:33:20]

DESTINY-Breast06: Trastuzumab Deruxtecan vs CT in Previously Treated HR+/HER2-Low or HER2-Ultralow MBC

DESTINY-Breast06. This is the T-DXd versus a chemotherapy in previously treated HR+/HER2-low, again a new entity, HER2-ultralow metastatic breast cancer. This is an open-label, randomized, phase III trial. Patients with metastatic breast cancer progressed on 2 or more previously endocrine treatment but no chemotherapy for metastatic. That is the key difference.

Here, the patients are exposed to endocrine treatment but no chemo in the setting. The second difference is HER2-ultralow based on the central IHC assessment was included, so 2 new entities. Patients who entered this trial. T-DXd, the same standard dose. Physician's choice, capecitabine/paclitaxel and nab-paclitaxel included.

A large study, nearly 900 patients with the primary endpoint of progression-free survival.

[00:34:36]

DESTINY-Breast06: Efficacy

Here, DESTINY-Breast06 clearly showed an improvement in progression-free survival when patients received T-DXd versus a treatment of choice. That is true in intent-to-treat treatment population. It is true in HER2-ultralow population. Based upon this data, clearly a new indication for a trastuzumab deruxtecan in HER2-ultralow population in first-line setting.

[00:35:12]

TROPION-Breast01: Dato-DXd vs TPC in Inoperable or Metastatic HR-Positive/HER2-Negative Breast Cancer

Here, this is looking at another ADC, Dato-DXd, TROPION-Breast01 trial. Dato-DXd versus treatment of physician choice in metastatic HR+/HER2- breast cancer.

Here the patients had 1 or 2 lines of systemic treatment and they are not eligible to endocrine treatment at that point. Then the patients were randomized between Dato-DXd 6 milligram per kilogram IV given every 3 weeks versus physician's choice of treatment.

PFS is the primary endpoint.

[00:35:51]

TROPION-Breast01: Primary Analysis of PFS, ORR, and OS

The study showed an improvement in progression-free survival, overall response rate. There was no difference in overall survival. But if you look at the overall response rate, it is almost 36% versus 22%. This is really clearly an option for HR+ positive patients who are exposed to 2 lines of chemotherapy in the metastatic setting.

[00:36:23]

TROPION-Breast01: Safety

It has some unique side effects, which we should be aware. It can cause stomatitis. Again, some GI side effects. Keratitis, dry eye, stomatitis are some of the unique side effects of Dato-DXd. Stomatitis, I think if you prepare the patient and then treat the patient with oral dexamethasone like we used to do for everolimus, I think even prophylactic that will help. If there is any concern with ophthalmology side effects, make sure the patients are seen by an ophthalmologist early on.

[00:37:07]

Patient Case 3: Recurrent HR+/HER2- MBC

Case 3, looking at another patient. 62-year-old post-menopausal patient with a history of hyperlipidemia, diagnosed with stage II breast cancer. She had adjuvant endocrine treatment with anastrozole for years. About 3 years after stopping the treatment, she developed bone mets.

Treatment was started with ribociclib/anastrozole. She was on that for about 2 years and then developed new liver mets. The genomic testing shows that ESR1 mutation.

[00:37:54]

Pretest 3

In your current practice, which of the following treatments would you recommend for this patient?

1. Fulvestrant + everolimus;
2. Elacestrant;
3. Imlunestrant + abemaciclib;
4. Capecitabine.

Okay. Elacestrant about 36%. Imlunestrant/abemaciclib about 37%.

I think I will pass this to Dr Kaklamani from here. No, I think there is one more question.

[00:38:41]

Pretest 4

Okay. Which of the following would you educate colleagues about regarding the safety profile associated with imlunestrant versus exemestane or fulvestrant? Dr Kaklamani is going to go over this in detail in the next few slides.

1. Increased diarrhea;
2. Increased hepatotoxicity;
3. Increased ILD/pneumonitis;
4. Increased ocular toxicity.

Okay. Some GI toxicity. Hepatotoxicity. Okay, good.

[00:39:43]

INAVO120: 1L Inavolisib + Palbo and Fulv vs Pbo + Palbo and Fulv in Patients With PIK3CAm HR+/HER2- LA/MBC

Dr Kaklamani: Perfect. Okay, so let us talk a little bit about some of the data that we have. One of the trials that actually we will see an update very soon, but there was a press release that showed that it also improves overall survival is the INAVO120 trial.

Now this is an interesting patient population, because this is in the first-line in patients that had endocrine-resistant disease. That was either progression during or after completing therapy for 12 months in the adjuvant setting. Not your garden variety, HR+ breast cancer patient that has disease recurrence.

Patients also have to have a PIK3CA mutation in their tumors. If that was the case, then they were randomized either to placebo, palbociclib and fulvestrant or the triple combination of inavolisib, palbociclib and fulvestrant.

[00:40:38]

INAVO120: Efficacy

When looking at the results of the trial, there was improvement that I think was very clinically meaningful with progression-free survival with inavolisib 15 months compared to 7.3 months with placebo. Highly significant. You can see the curve separating early.

You can also see that both groups did worse than we would have seen in that first-line metastatic CDK trials because they had endocrine-resistant disease and because they also had tumors that had a PIK3CA mutation.

[00:41:11]

INAVO120: PFS by Subgroups

This is a subset analysis and we are looking at all the different subsets. The bottom line is that regardless of what was looked at, patients benefited from the addition of inavolisib. Inavolisib was approved based on this clinical trial and I personally have not used it yet just because this is a small subset of patients, but I definitely would if I had a patient that fit the criteria for the INAVO trial.

[00:41:36]

INAVO120: Adverse Events

Now whenever we add a medicine, we also add toxicity. What are we adding with the addition of inavolisib? Inavolisib is another PI3 kinase inhibitor. It has those 4 toxicities that the class has: diarrhea, hyperglycemia, stomatitis and rash.

What is the major toxicity? Hyperglycemia. We are going to see hyperglycemia here. The patients were very selected for a hemoglobin A1C of less than 6 to be able to be on the INAVO trial. Very good selection and be careful because that is also extremely important.

Now the rash tends to be very dose limiting or dose sensitive. If we lower the dose, we can improve, but we can also give antihistamines. Stomatitis, we can give the steroidal mouthwash, not a major issue there.

[00:42:24]

ESR1 Mutation Is Associated With Poorer Prognoses

Now, we mentioned the ESR1 mutations. What are these ESR1 mutations and how important are they? These are mutations that happen in the ligand binding domain of the estrogen receptor and they make the estrogen receptor active regardless of whether there is a ligand or not.

They also make the cancer more endocrine resistant. The prognosis of patients that have tumors with ESR1 mutations is worse than if the tumors were wild-type. You can see this data here from clinical trial data looking at both progression-free and overall survival.

[00:43:05]

EMERALD Phase III Trial of Elacestrant vs SoC in ER+/HER2- MBC: PFS by Subgroups

Now the EMERALD trial was a trial looking at elacestrant, which is an oral SERD that targets the estrogen receptor in a better way than other endocrine therapy. It is more active in patients that have tumors with the ESR1 mutations. It showed exactly that that elacestrant outperformed the standard of care endocrine therapy in patients that had tumors with ESR1 mutations.

Now that improvement was really irrespective of any other subsets. What we want to be thinking about with elacestrant is these ESR1 mutated tumors.

[00:43:41]

EMERALD: AEs Summary

Now what happens when we give elacestrant? We have some GI toxicities. We can have a little bit of nausea vomiting, some GI upset. Most of it is grade 1 and 2, very few grade 3 or 4 toxicities as you can see here.

Actually, the use of antiemetics was less with elacestrant than it was with the aromatase inhibitor on the EMERALD trial.

[00:44:04]

EMBER-3: Imlunestrant ± Abemaciclib vs SoC ET in Patients With ER+/HER2- ABC After Progression on ET

Other oral SERDs are coming. Imlunestrant is the second one. This is data from the EMBER-3 trial looking at imlunestrant with or without abemaciclib comparing that to standard of care endocrine therapy in patients that have metastatic HR+ breast cancer.

[00:44:01]

EMBER-3: PFS for Imlunestrant vs SoC ET  (Primary Endpoints)

Now a little different in the trial as a design, but the bottom line is the same, single agent imlunestrant. I performed standard of care endocrine therapy and that was only seen in the patient population that had tumors with ESR1 mutation. So exactly what we saw with EMERALD.

[00:44:41]

EMBER-3: PFS for Imlunestrant + Abemaciclib vs Imlunestrant (Primary Endpoint)

Then when looking at the combination arm and comparing that to single agent imlunestrant, because that was the trial design, there was an improvement when we added abemaciclib as expected, and that improvement was actually pretty high. There was a median PFS of 9.4 months compared to 5.5 months with single agent imlunestrant.

That improvement did not have anything to do with the presence or absence of ESR1 mutations. We can potentially use the combination regardless of an ESR1 mutation.

[00:45:14]

EMBER-3: Safety of Imlunestrant vs SoC ET

As far as safety, the 1 potential toxicity within imlunestrant, there is going to be a little bit of GI side effects as you can see here. But the one thing to keep in mind is that there could be some visual changes, but very few. Most of the visual changes that we have seen with the oral SERDs is from the third oral SERD that we are going to have data in the next few weeks, which is called camizestrant.

A little bit of GI toxicity here with imlunestrant. Obviously, when you are combining it with abemaciclib, you are having more GI toxicity there.

[00:45:52]

EMBER-3: Safety of Imlunestrant + Abemaciclib

This is the combination arm, and obviously some cytopenias but also some GI toxicity because of the potential adverse events that we see with abemaciclib.

[00:46:05]

Patient Case 3: Recurrent HR+/HER2- MBC

Let us revisit that third case. 62-year-old post-menopausal patient, history of hyperlipidemia, diagnosed with stage II breast cancer, receives adjuvant endocrine therapy with anastrozole for 5 years. Three years after finishing therapy, she developed metastatic disease.

She started on ribociclib and anastrozole. Now she has genomic testing that shows an ESR1 mutation.

[00:46:27]

Posttest 3

The question is should we give her:

1. Fulvestrant + everolimus;
2. Elacestrant;
3. Imlunestrant + abemaciclib; or
4. Capecitabine.

A lot of people are going to give him imlunestrant/abemaciclib. Remember, it is not approved yet, but it is likely going to be approved in the next several months.

For now, I would consider the standard of care being elacestrant here since this is the approved agent, but we will see how the data will evolve with the combination of imlunestrant and abemaciclib. At least the data from member 3 looks very, very promising.

[00:47:35]

Posttest 3: Rationale

Yes, elacestrant is the correct answer just because that is the drug that we have approved at the moment.

[00:47:43]

Posttest 4

Now, which of the following would you educate your colleagues about regarding the safety profile of imlunestrant versus exemestane or fulvestrant?

1. Increased diarrhea;
2. Hepatotoxicity;
3. ILD/pneumonitis; or
4. Ocular toxicity.

Yes, I am seeing some diarrhea, hepatotoxicity here. I think that is pretty much what we are seeing when we are treating patients with imlunestrant. A little bit of diarrhea. Most of it is going to be because if we combine it with abemaciclib, the effect of abemaciclib, it is usually a well-tolerated agent.

I will pass this on to Dr Abraham for the final part of our talk.

[00:48:51]

A Look Into the Crystal Ball: How the Breast Cancer Treatment Algorithm May Change in 2025

Dr Abraham: Thank you, Dr Kaklamani. When we look at some of the exciting trials, which is happening or some actually we already have some press release on some of these trials listed here.

[00:49:04]

Key HR+/HER2- Breast Cancer Trials on the Near Horizon

TRADE, as Dr Kaklamani mentioned when she was talking about adjuvant, that is looking at the dose escalation strategy starting with 50 milligram BID dose of abemaciclib in adjuvant setting, increasing that 1 or 2 weeks and then increasing that to a 100 milligram BID and then escalating from there.

I think that will be a really interesting study, especially in high-risk patients who meets the inclusion criteria for a monarchE with the long-term follow up, if you really want to give abemaciclib. I think that will be really an important study.

SERENA-6, I am sure some of you have seen the press release from AstraZeneca in February, a couple of months back, which actually showed an clinically meaningful improvement in PFS in first-line advanced HR+ patients with ESR1 mutation. That is again really interesting study where camizestrant is combined with an aromatase inhibitor in combination with the CDK4/6 versus an AI. Hopefully, we will have more publication and more data coming out.

VERITAC trial, another estrogen receptor degrader. I think that field is really expanding so rapidly. That is another exciting trial. That is looking at fulvestrant versus the estrogen receptor degrader. We will wait for data from that trial too.

[00:51:01]

Panel Discussion: HR+/HER2 MBC

I think that is what we have and we will look at Dr Kaklamani. Any thoughts about based upon these data, I know you mentioned some of these drugs are not approved like imlunestrant. But based upon the INAVO, have you started using that in first-line setting yet?

Dr Kaklamani: I would if I had the patient. I have not had a patient yet, but yes, I think the data looks pretty impressive and, again, we will see some overall survival data at ASCO as well. I think one of the questions that came in was question about whether imlunestrant will be approved as a single agent or with abemaciclib. Your guess is good as mine? I have no idea.

It would also be interesting to see whether the FDA approves it for all comers in combination or just for ESR1 mutated tumors. We will see. I think they are still looking at the data and they probably need a little bit more follow up, but they have not given an indication yet as to what they will do.

Dr Abraham: That will be really interesting. I think that field is changing so rapidly and it is really good news for our patients. If I can ask you, let us just say if you are seeing a 48-year-old patient who was on let us just say letrozole for the last 4 years, now metastatic disease. You did a biopsy and that has a PIK3 mutation. Then as first-line metastatic setting, you will start palbociclib, inavolisib and fulvestrant at this point? Or you will wait for a sequential approach?

Dr Kaklamani: As long as they meet the criteria for INAVO120, and again, as long as their hemoglobin A1C is low, and I practice in south Texas, so I do not know that I see a lot of patients with the hemoglobin A1C of less than 6. But yes, I mean these are patients that have endocrine-resistant disease that as you saw, just with a dual combination of a CDK4/6 inhibitor and endocrine therapy, the median PFS was 7.3 months. It is low. We need something more. These are aggressive tumors.

Dr Abraham: Right. Fully agree. Anything else you are really excited for this year and anything exciting in ASCO?

Dr Kaklamani: We are going to see SERENA-6. The press release is positive. It is actually going to be a plenary session, so I would assume the data looks pretty good. We are also going to see, as you mentioned, the VERITAC data. That will be nice to see another single agent endocrine therapy.

Later this year, we will have a lot of other data. We will have data with antibody drug conjugates, which I think will be pretty impressive. It is going to be a very heavy year as far as trial reporting. I think it will be pretty cool.

Now there are a couple of questions I will ask you that people were asking. First of all, if you are giving T-DXd, would you sequence that after progression to sacituzumab or would you switch to something else? How are you looking at this switch between ADC and ADC?

Dr Abraham: I know. I do not have a data-driven answer for that, but let us just say if I am treating somebody with T-DXd and if they progress, there is no overlapping toxicity, I may switch to sacituzumab. Again, it is all depending upon the toxicity and tolerability for that patient. What do you think? How do you do it?

Dr Kaklamani: We do not have any randomized clinical trial data. There is trials going on now, so we will have results at some point. My concern is a Topo I inhibitor after a Topo I inhibitor is not going to produce exceptional results. That is what we saw with the real world data that the median PFS with the second Topo I inhibitor, regardless of which one it is, it is around 3 to 4 months.

We are getting very little benefit from that second-line. But at the same time, we are not going to get a huge benefit from chemotherapy either. I personally give the second ADC as long as the patient is doing well and I feel is a candidate for an ADC, but I would love be able to use an ADC that has a different payload.

Dr Abraham: I know we had some real-world data in the last San Antonio meeting, I think do not know if you are part of the same, and it is from UT Southwestern came out, and so that was interesting. But you are right, it is limited data.

Dr Kaklamani: There was another interesting question about giving a GnRH agonist and whether we are checking estradiol levels or not. Do you usually check estradiol levels, or do you base things on patient symptoms?

Dr Abraham: That is interesting. Actually, a few years back, we had intense discussion in the NCCN committee about who is checking and who is not checking. It is half the committee members said, no, we do not check. Half said, we do check.

There is question about the validity of the tests too and how reliable, how it is fluctuating. But really, here the question is actually I think patients under the age of 30 or really young patient. Young patients, I really worry. If I am really suppressing the ovarian function with an injection, let us just, somebody is under the age of 35, I may check it, but not routinely. Somebody is under the age of 45 or 50 and premenopausal, I do not check it routinely. What do you do? How do you do it?

Dr Kaklamani: Yes, I do not check either. I ask patients.  If they have any symptoms, I ask patients to make sure that they are not spotting or menstruating. Obviously, if I do an estradiol assay, as you mentioned, I need to do the ultrasensitive one, the liquid chromatography. That is something that you would have to request especially, not just send the regular one. I typically just go with patient's symptoms. I do not usually check estradiol levels.

Dr Abraham: This is a good question, as we all know well, about 14% or 15% of patients can have breakthrough. I think, as you said, we should be paying attention to this and asking patients these questions. You are right, yes.

Good. Very good. I think we are almost coming to the end. Any final word, Dr Kaklamani from your side?

Dr Kaklamani: I would just say this used to be a boring part of breast cancer, because we had a couple of agents. Now it is the most exciting part. We are using genomic testing. We are using all of these new agents. I think SERENA-6 will be pretty provocative, although the initial result is just going to be the first PFS. I would love to see PFS 2, which hopefully will be presented later this year. This is exciting. This is fun for all of us.

Dr Abraham: Absolutely. As you mentioned, keep an eye for all the ADC data. T-DXd has a lot of data coming out and possibly at ESMO and hopefully at San Antonio. Dr Kaklamani, you run that meeting, so there will be some exciting data coming out with T-DXd in 2025 also.