Here is the landscape over the last 26 years or so, with tamoxifen being introduced in 1970 and 80 in the metastatic and adjuvant setting, respectively, and then the aromatase inhibitors first for metastatic and then in the adjuvant setting, and the later 90s. Then fulvestrant about 25 years ago.

Now then, we had the exemestane everolimus combination in 2012. The CDK4/6 inhibitors were introduced about 10 years ago now 2015 to 17. Then alpelisib, the PI3 kinase inhibitor in 19, and then in 23, the first oral SERD elacestrant, and also the AKT inhibitor capivasertib. Inavolisib in 24 PI3 kinase inhibitor, the second oral SERD imlunestrant.

Just recently in 25, and then very recently in the past few weeks, vepdegestrant, the oral PROTAC, which also degrades the estrogen receptor. There is really been a lot of activity and a lot more to come as we will look at as well going forward as we look forward to getting more combination strategies available as well.

Unmet Need for Targeted Treatment Options in HR+/HER2- MBC After 1L Treatment

I know we all agree that we have a lot of unmet need for targeted treatment option. Our diagnostics are getting better and better, picking up mutations that are driving resistance to endocrine therapy. We just need strategies now to be as effective as the CDK4/6 inhibitors and the aromatase inhibitors in that first-line setting, where patients are getting up to 28 months of median progression-free survival.

This has just been a really fabulous advance for patients. The problem is, of course, that median progression-free survival drops by about 80%. As we get into the second-line setting third-line setting were two to six months in most of the trials, and then even our chemotherapy. When we transition to chemotherapy, we are still getting median PFS in the four to eight-month range. Once resistance develops to the AIs and to the CDK4/6 inhibitors, we can understand what some of those mechanisms are, but we really need increasingly effective therapies to get more durable control of the disease after progression on that first-line CDK4/6 inhibitor.

ESR1-Mutated Estrogen Receptor

Enter the estrogen receptor mutation. ESR1 mutations are very common after our patients have disease progression on AI plus CDK4/6 inhibitor, up to 20% to 30%. In the ELEGANT trial where everyone had AI plus CDK4/6, and they received elacestrant versus standard of care endocrine therapy. Second, third-line, it was 50% of patients had an ESR1 mutation. It is really very high.

The development of this mutant estrogen receptor. This continues to increase over time. If they do not have an ESR1 right after their first-line, they can still develop one down the road. Whereas in endocrine therapy, naive metastatic breast cancer, so de novo metastatic disease would be very unusual in AI pre-treated first-line metastatic disease, I have seen from 5% to 15%.

It is a range in AI pre-treated patients, because taking away that ligand really is what leads to the selective pressure on the estrogen receptor and the outgrowth of clones that are mutant, do not need the ligand, do not need the estrogen, because the wild type estrogen receptor requires the estrogen in order to have a homodimerization and lead to transcription.

The mutant estrogen receptor is mutated in the ligand-binding domain shown here. The biggies are the Y537S, and C, and H, and also the D538G. These are the two most common ones, but they rendered the estrogen receptor constitutively active. It does not need the ligand at all. AIs are completely ineffective in the context of an ESR1 mutation because transcription just drives. Now it is still ER-driven. Breast cancer is still very much about the estrogen receptor. It is just a really, really powerful estrogen receptor. It is a target, a very important target for therapy.

Combining Targeted and Antiestrogen Therapies to Overcome Resistance in HR+ Advanced Breast Cancer

Now there is other mechanisms of endocrine therapy resistance. We have got the ESR1 activating mutations very important. We can see cyclin D1 amplification FGFR1 amplification, which we really cannot target yet. Activating mutations in PI3 kinase AKT, loss of PTEN mutations in HER2.

Of course, we are very interested in building combinations to either inhibit the wild type ER in combination with one of these other resistance pathways targets and/or to go after the mutant estrogen receptor in combination with PI3 kinase AKT mTOR inhibitors in particular, as well as going on from one CDK to another.

Building a combination strategy is very important because though the ESR1 may really be the dominant mutation, and I think we are evolving in our understanding that this indeed may be the real dominant mechanism of resistance, it does keep company with a number of other alterations. We will look at the data, and we will see that when we do combination strategies, we do have better progression-free survival than just inhibiting the ESR1 mutation by itself.

ESR1 Mutations in Advanced Breast Cancer

What is the incidence of the ESR1 mutations? If we look down here, the MONALEESA-2, as you recall, is a first-line metastatic trial of letrozole and ribociclib. Only 4% of patients had an ESR1 mutation in that trial. In these other trials, where patients had been pre-treated on endocrine therapy, it ranges here between 25% and 40%. If we had elacestrant - EMERALD trial on this list, it would be up to 50%. It really is quite common. Now, we will not find it in the primary breast cancer less than 1%. It is truly an acquired mutation. We are not going to have a lot of help by going back to the original breast cancer primary archival specimen and looking for an ESR1 mutation.

Posttest 1

Let us go back to that question about how would you explain to a colleague why next-generation SERDs remain effective in ER-positive, HER2-negative advanced breast cancer after ESR1 mutations emerge on AI therapy

1. Block estrogen from binding ER alpha without degradation of the receptor;
2. Bind directly and degrade ER alpha blocking activity independent of estrogen;
3. Inhibit ER alpha transcriptional activity; or
4. Suppress estrogen production more completely than AI.

What do you think?

That is great. That is the correct answer. It is direct binding to the estrogen receptor, the next generation oral SERDs, and leading to degradation of ER alpha blocking activity independent of the presence of estrogen because it is constitutively active.

Pretest 2

Then let us go ahead and take a look at the data that informs our currently available oral SERD, and now our PROTAC, as well the vepdegestrant. Here is a question about the VERITAC-2 trial. Based on the phase 3 VERITAC-2 trial comparing vepdegestrant versus fulvestrant, which patient population with ER-positive HER2-negative metastatic breast cancer? Would you consider vepdegestrant monotherapy?

1. After progression on first-line endocrine therapy regardless of ESR1 mutation status;
2. ESR1 mutation positive after progression on endocrine therapy plus CDK4/6 inhibitor.
3. After two or more lines of endocrine therapy, including with a CDK4/6 inhibitor, regardless of ESR1 mutation status; or
4. ESR1 mutation positive after two or more lines of endocrine therapy, including with CDK4/6 inhibitor.

What would be the place you would want to position that vepdegestrant?

It is split between after first-line or after second-line. We will come back and have a look at that.

Mechanisms of Action of Different Endocrine Therapies

We have lots of ways to inhibit the estrogen receptor here in the top left. This is the wild-type estrogen receptor. I do not know if my mouse worked there. It is the wild-type estrogen receptor estrogen leading to homodimerization, binding to the estrogen response element, engaging AF1 and AF2 coactivators, and leading to gene transcription.

The AI, as we are well aware, stopped the conversion of androgen precursors from the adrenal gland into estrogen, so it takes away the ligand or at least reduces it. The SERMs tamoxifen in particular, bind to the estrogen receptor and homodimerizes goes into the nucleus, inhibits AF1 and also recruits an co-repressors and shuts down ER transcriptional activity that drive the breast cancer, but also can activate transcription in other organs such as the bone and the liver, which can have salutary effects for the patients.

The SERDs also bind the estrogen receptor, do not make it to the nucleus. They get degraded by the proteasome in the cytoplasm, so they do not make it into the nucleus to drive transcription. The PROTACs are these very ingenious molecules where one end, here in the blue binds to the estrogen receptor, and the other end of this molecule in blue binds to the E3 ubiquitin ligase.

It binds here to the estrogen receptor and binds to the E3 ligase and brings them in very close proximity, allowing this ligase then to easily ubiquitinate. The estrogen receptor, once it is ubiquinated, it is destroyed by the proteasome. Then, interestingly, the PROTAC is recycled within the cell very clever, unique mechanism of action. The SERCAs, I am not aware of a SERCA being currently developed in clinical trials. Maybe we will see another one in the future, but it leads to a unique conformational change of the estrogen receptor. That is a very strong antagonist.

It does bind to the DNA, but it is a very strong antagonist. Then lastly, the CERANs, such as palazestrant, which we will talk about, binds to the estrogen receptor leads to ER degradation. Also, as I will show you really shuts down transcription from ER fully by blocking both AF1 and AF2, these two coactivators, so multiple mechanisms of activity there.

EMERALD: Elacestrant vs Investigator’s Choice SoC ET in ER+/HER2- MBC

Let us just review some of these important data that inform our practice, the phase 3 EMERALD trial, the first trial of an oral SERD elacestrant versus investigator's choice of endocrine therapy, which was fulvestrant or an AI. The vast majority of patients got fulvestrant. They were required to have had a prior CDK4/6 inhibitor, one to two lines of prior endocrine therapy, at least one with a CDK4/6 inhibitor, a 1:1 randomization, 345 mg of the elacestrant, and the primary endpoints were PFS in the full population, as well as in the ESR1 mutant population, which was about half of the patients.

EMERALD: PFS With Elacestrant vs SoC in ITT and
Population With ESR1mut+ Disease

In all patients, there was an improvement in median progression-free survival. We can see here, for example, the 12-month progression-free survival rates, nine months versus 22 months. Really, that was driven in terms of superiority. It was driven by the ESR1 mutant population. This was also statistically significant, but really it was driven by the ESR1 mutant in terms of the real benefit from the elacestrant.

We can see again at 12 months, 8% of patients progression-free, versus really triple more than triple that. There still is about 40% of patients here, you see, by their first scan, who have not benefited from the elacestrant. It is going to be important for us to understand over time who these patients are.

This was a clear demonstration, and most of us felt that these patients were like, at this point, really endocrine therapy resistant. We are not going to benefit, but those who still had disease that was really driven by this mutant ESR1 really were benefiting much more than they were from fulvestrant.

EMERALD Subgroup Analysis: PFS by Subgroup in ESR1m Patients With ≥12 Mo of CDK4/6i

One of the hints that came from EMERALD in terms of who really would benefit and not have that steep as drop or as deep a drop, I should say by the first scan was patients who had been on their prior CDK4/6 inhibitor for at least 12 months. Those patients with more endocrine therapy-sensitive disease had an 8.6-month median progression-free survival in the ESR1 mutant population.

That is really quite good compared to about two months with fulvestrant alone. This is how we now really try to enrich for patients who are going to benefit from single-agent elacestrant. We look for these patients who had at least a year on their prior CDK 4/6 inhibitor. The ESR1 mutant with liver or lung and or lung metastasis 7.3 months. Co-mutant for ESR1 and PIK3CA 5.5 months median PFS.

The P53 does not seem to make a difference compared to ESR1 mutant alone, so those patients did well 8.6 months. Again, HER2 low status did not make a difference at HER2 low did not seem to be driving resistance to inhibition of that mutant ESR1. These numbers are really quite decent, so finding this population here really helped us in practice enrich for the population that is going to benefit from elacestrant.

EMBER-3: Imlunestrant ± Abemaciclib vs SoC for ER+/HER2- ABC

We will talk a little bit later about some of the combination strategies going on. The more recent oral SERD to come to us in practice is imlunestrant because of the EMBER 3 trial. These patients have had progression on first-line endocrine therapy with or without a CDK 4/6 inhibitor, or they could have recurred within a year of finishing their adjuvant AI with or without CDK4/6 inhibitor.

About 60% of patients in this trial had had a prior CDK4/6 inhibitor. This was second-line therapy, and they were randomized to imlunestrant, another of the oral SERDs, versus imlunestrant plus abemaciclib, the CDK4/6 inhibitor, versus standard of care, fulvestrant or exemestane. Again, most patients received the fulvestrant. There were two co-primary endpoints comparing imlunestrant with standard of care, endocrine therapy or imlunestrant to imlunestrant plus abemaciclib.

EMBER-3: PFS and OS With Imlunestrant Alone vs SoC

If we look first at progression-free survival and overall survival with imlunestrant alone versus standard of care, we see a nice improvement in median progression-free survival, with 3.8 months with standard of care up to 5.5 months. This is in the ESR1 mutant population. Again, we saw in number three that in the ESR1 wild-type population, there is a trend towards improved benefit with the imlunestrant as there was with elacestrant, but the real statistical superiority of the oral versus fulvestrant comes in the ESR1 mutant population.

Again, we see here about 30% of patients not benefiting at the time of that first scan, then the curves split. What is interesting and I think noteworthy and good for us to know about is at the final overall survival analysis from EMBER-3, at a median follow-up of 28 months, the patients with ESR1 mutations, the median overall survival was 34.5 months with elacestrant versus 23.1 months with standard of care, endocrine therapy hazard ratio 0.6. It was statistically significant. Also, in the overall treated population, we see the same trend. This is a pretty impressive 11 month improvement in overall survival in the ESR1 mutant population. I think that is worth knowing about.

EMBER-3: PFS by Subgroup

What about subsets in the EMBER-3? Now we are looking at imlunestrant versus imlunestrant plus abemaciclib. In the patients with an ESR1 mutation, it is 5.5 months. With imlunestrant, it goes up to 11.1 months with the addition of the abemaciclib. That is really getting very gratifying in terms of seeing this duration of almost a year of median PFS. Those who did not have the ESR1 mutation quite good, 9.2 months.

These agents are particularly beneficial against the ESR1 mutations, now the co-mutation of ESR1 and PIK3CA - no, sorry. This is just PIK3CA alone is 7.6 months, a doubling of median PFS without the PIK3CA 11.3 months. Really suggesting that these inhibitors of the ESR1, is also a PIK3CA around really will work best in combination.

Though it is only 68 patients here, this co-mutant population is certainly very provocative at 16 months median PFS with and 3.8. It is interesting because abemaciclib, the CDK4/6 inhibitors, are downstream from the mutant PI3 kinase. That pathway basically generates proliferation and transcription through the through CDK4/6. Blocking CDK4/6 with abemaciclib downstream from this mutant PI3 kinase appears to be quite effective here in combination with imlunestrant.

Novel Agent for ESR1-Mutated MBC: PROTAC ER Degrader

Then let us turn to the PROTAC, another ER Degrader. We will review the VERITAC data here.

VERITAC-2: Vepdegestrant vs Fulvestrant in ER+/HER2- Advanced BC

Directly comparing now, vepdegestrant to fulvestrant. That was the only option here. These patients had had one line of prior therapy with the CDK4/6 inhibitor. One additional line was permitted, but that second-line, the most recent endocrine therapy, had to be given for at least six months before disease progression, so enriching for a more endocrine therapy sensitive population. It was a 1:1 randomization 200 mg daily of vepdegestrant versus standard fulvestrant, and the primary endpoint was co-primary PFS in the intent-to-treat population as well as in the ESR1 mutant population.

VERITAC-2: PFS

If we look here at the ESR1 mutant population, again, we see this fall off in about 30% of patients not benefiting. Then the curve split. We see a very persuasive improvement in progression-free survival. The medians here are 2.1 month median PFS versus five months, a hazard of 0.57. We see the significant p value.

Again, in all patients, there is a trend in favor of the vepdegestrant, but again, the superiority of this agent is in the context of the ESRI mutation. It is really quite superior to the other SERD, fulvestrant, which has some partial activity against some of the ESR1 mutations. This PROTAC is really much superior to fulvestrant.

VERITAC-2 Subgroup Analysis: PFS by Subgroup in Patients With ESR1m

What about subsets in the VERITAC? Again, this is the all ESR1 mutant population 2.1 versus five months median PFS. Now with liver metastasis here, 122 patients, not a lot of difference. The hazards 0.5, but the medians are not that different without liver metastasis. A nice improvement here.

In those patients that are mutant for ESR1, and an alteration in PI3 kinase AKT or PTEN. Again, not as strong a signal suggesting that we really are going to optimally help patients with blocking this pathway simultaneously, and also without the PI3 kinase AKT, PTEN alteration 5.5 months with the alone.

Again definitely superior to the intramuscular SERD that we have had here for patients. May 1st, 2026, FDA approved vepdegestrant for adults with ER-positive HER2-negative metastatic breast cancer with an ESR1 mutation and disease progression following at least one line of endocrine therapy.

Treatment Algorithm for HR+/HER2- MBC

What might our algorithm be for treating HR positive HER2 negative metastatic breast cancer? Of course, we are going to always start off with the CDK4/6 inhibitor in the first-line setting in combination with an AI. If they have not recurred on an AI or with fulvestrant. If they have recurred on adjuvant AI therapy, and they have a PIK3CA mutation and they have a hemoglobin A1c less than 6%, then we really want to consider the addition of an inavolisib to palbociclib and fulvestrant, because of the very nice survival advantage found with the addition of the PI3 kinase inhibitor to this doublet here.

In second-line things splay open, and we really need to have NGS on tissue, but also ctDNA to try to understand what resistance mutations that are targetable may be apparent in the patient's cancer at that time. If the patient is PIK3CA, AKTP/PTEN, and ESR1 wild type, they are eligible for an AI, fulvestrant, or fulvestrant and everolimus.

The imlunestrant and abemaciclib combination was studied and is more effective than imlunestrant in this patient population, so this is actually in the EMBER-3. This population was in EMBER-3. For ESR1 mutant patients. We certainly would be thinking about single agent elacestrant, imlunestrant, or vepdegestrant post progression on CDK4/6.

We also have seen that the imlunestrant and abemaciclib combination is also very active in this group of patients as well. If the patient's cancer has an alteration in the PI3 kinase pathway, fulvestrant plus capivasertib fulvestrant plus alpelisib, much less commonly used these days.

Also plus abemaciclib actually would fit into any of these boxes because all of these populations were included in the EMBER-3 trial, which looked at imlunestrant plus minus abemaciclib. Then we tend to go on in the third-line to what we did not do in the second-line setting. We could also put fulvestrant and abemaciclib here in the second-line setting based on the postmonarchE trial.

If we inhibit the PI3 kinase pathway in the second-line setting, we may go to abemaciclib in the third-line, if the patient had palbociclib or ribociclib in the first-line setting. We certainly want to be looking for germline BRCA mutations, germline PALB2 mutations, and somatic mutations in BRCA 1 or 2, so we could use a PARP inhibitor in some patients. Some patients will require chemotherapy or antibody drug conjugate by third and fourth line, certainly.

Posttest 2

Let us go back to that question we had earlier, which is that based on the phase 3 VERITAC-2 trial comparing vepdegestrant versus fulvestrant, which patient population with ER-positive HER2-negative metastatic breast cancer would you consider vepdegestrant monotherapy for?

1. After progression on first-line endocrine therapy regardless of ESR1 mutation status;
2. ESR1 mutation positive after progression on endocrine therapy plus a CDK4/6 inhibitor;
3. After two lines of endocrine therapy, including with a CDK 4/6 inhibitor regardless of mutation status; or
4. ESR1 mutation positive after two or more lines of endocrine therapy, including with CDK4/6 inhibitor.

What would be your choice.

That is right. It is after at least one line was the FDA label. Most of the patients received this second-line. We could do it later. We could do it after a couple of lines of endocrine therapy, bit it really is after that first-line that most of the patients were studied in VERITAC-2.

Community Challenge

Here is another question here. What is the most common or pressing challenge you face when integrating next-generation ER-directed therapies into treatment sequencing?

1. Barriers to adherence;
2. Delays in molecular testing reports;
3. Identification of multiple actionable mutations.

It is all, but particularly delays in molecular testing, but also the identification of multiple actionable mutations, trying to understand which one may be dominant, which one to particularly target in the absence of opportunity to target multiple mutations.

Advancing Outcomes With Emerging Next-Generation Approaches to Targeting the ER

Let us talk about the emerging next-generation approaches, particularly some of the novel combination strategies here.

SERENA-6: CDK4/6i + Camizestrant or AI in ESR1m HR+/HER2- MBC in Patients Without PD on 1L CDK4/6i + AI

This is the SERENA-6 trial that we remember from the plenary session at ASCO 2025 last year. It is a very interesting novel design for patients in the first-line, metastatic HR positive HER2 negative setting who are doing well. They had to be on their AI plus CDK for at least six months, doing well, no evidence of progression.

They started undergoing ctDNA evaluation every two to three cycles, they would have blood drawn to survey for the emergence of an ESR1 mutation. When one was found, they underwent staging evaluation to make sure that their disease was stable, that there was no evidence of clinical progression on imaging.

If they were still stable. They had molecular progression but not clinical progression, they were randomized to continue their same AI plus CDK until the time of clinical progression. This was placebo-controlled versus switch to camizestrant, another of the oral SERDs, so targeting that resistance mechanism, going after that ESR1, continuing their same CDK4/6 inhibitor. Again, placebo-controlled primary endpoint was progression-free survival. 312 patients were randomized, 3000 were screened in order to find these 300 who had the ESR1 who had not had disease progression.

SERENA-6 Update: Survival and ESR1m ctDNA Outcomes

The study met its primary endpoint. You can see here a very nice split in the curves. The median PFS patients went another 9.2 months on AI CDK before progression on imaging or clinical progression versus 16.6 months switching over to camizestrant. If we look at this two year mark, for example, only 5% are progression-free.

Sticking with the AI plus CDK in the context of an ESR1 mutation versus 30%, that is a big difference here in the percentage of patients progression-free. Switching over to target that ESRI mutation. If we look at PFS two and we are going to see updated data here at ASCO on the final PFS two data, but adding in the progression-free survival with what happened with their next therapy after they progressed on their camizestrant and CDK versus AI plus CDK, it is 19.4 months with AI CDK versus 25.7.

That was also highly statistically significant. Then, chemotherapy ADC free survival was 18.7 versus 22.7 months. This is obviously a positive trial. ODAC on April 30th voted against, not unanimously, but voted against recommending camizestrant for use in this first-line setting.

The FDA just announced it is going to extend its review process. There is additional data that they will be looking at here, some of which we will see at ASCO this year. I am still keeping my fingers crossed on this one. Here we will see the final phase 2 data on June 2nd in the oral abstract session, so stay tuned on that.

evERA BC: Giredestrant + Everolimus in ER+/HER2- ABC Previously Treated with CDK4/6 Inhibitor

evERA is a positive trial, and we are waiting for FDA approval on giredestrant and everolimus. Giredestrant, of course, another of the oral SERDs. These patients again, HR positive HER2 negative metastatic breast cancer, one to three lines of prior therapy, with two or fewer lines of endocrine therapy for metastatic breast cancer.

They all had to have had a prior CDK4/6 inhibitor, no prior chemotherapy for metastatic disease, 373 patients, and this was a randomization to the combination of standard of care endocrine therapy, which was fulvestrant mainly, but also a good cohort, a good - mostly of exemestane, but also some fulvestrant, which I will show you in combination with the mTOR inhibitor everolimus at full dose 10 mg versus giredestrant 30 mg daily with everolimus. This was in patients who had an ESRI mutation and those who did not. It had co-primary endpoints. Investigator assessed PFS in the intent-to-treat population and in the ESR1 mutant population.

evERA BC: INV-Assessed PFS in ESR1m Population

What we are looking at here is the ESR1 mutant population, which is really very interesting that we see this really big improvement. Even with a doublet. It is oftentimes hard to show a really big contribution of changing one agent in the context of two together. We really see a big improvement from 5.4 months median PFS with standard endocrine therapy, everolimus up to 10 months with the giredestrant and everolimus.

For patients without an ESRI mutation, there was basically no difference. A little bit of a trend, but basically no difference in median progression-free survival. Again, we are seeing the superior activity of the oral SERD against the ESR1 mutation. Again, here at 12 months 40 versus 15% of patients progression-free. Very nice. Here it is down here, looking at the patients 67 with exemestane, 31 with fulvestrant a 2:1. We see the point estimate for PFS the same at 0.44. Regardless of what the standard endocrine therapy chosen was, giredestrant was substantially better.

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

Now looking at subgroup analysis again, all patients with ESR1 mutation the hazard of 0.4 ESR1 mutation not detected. Then this is the intent to treat. We will start with the ESR1 mutation. Here we see that regardless of the duration of the prior CDK4/6 inhibitor, less than 12 months, 12 to 24, or more than 24, we have the same hazard ratio.

This did not really seem to make a difference in combination putting the giredestrant together with the everolimus, and it did not seem to make a difference either. What the prior CDK4/6 inhibitor had been. We still see good benefit from the giredestrant, and that was also true in the intent to treat population, but really the differential benefit with the giredestrant was clearly in the ESR1 mutant population.

Novel Agents for ESR1-Mutated MBC: Complete Estrogen Receptor Antagonist

Let us take a look at the CERANs. This is palazestrant. It turns out that all of these driving pathways we see here that we are very familiar with, they signaled down and they can activate and phosphorylate AF1. One of the co-activators for the estrogen receptor complex. Here is the DNA-binding domain of the estrogen receptor.

We got these two activating sites. Tamoxifen binds the estrogen receptor in such a way that it turns off AF2. It does not turn off AF1. The CERAN, which is a complete antagonist, binds to AF2, turns it off, which in turn conformationally changes the structure of AF1 and also turns it off. It is a complete transcriptional shutdown. It also leads to degradation of the estrogen receptor.

OPERA-01: Palazestrant vs SoC in ER+/HER2- Advanced BC

There are two trials going on with palazestrant. This is in the second-line setting, patients previously treated with endocrine therapy plus CDK4/6 inhibitor. They are randomized to standard of care single-agent endocrine therapy versus palazestrant. This trial has completed enrolment. We are waiting for the PFS in this population.

Ongoing and Completed Trials of Novel Oral Endocrine Therapies

Then I will show you in a second what the other trial is. Just to take a look at other data sets going to be coming our way, this is a of the ElCIN trial for those patients with elacestrant single agent who have received endocrine therapy, but not prior CDK4/6 inhibitor. That would be very interesting. The big adjuvant elacestrant trial, which is enrolling very well.

It is a switch trial after two to five years of standard endocrine therapy, switching to more of the same versus switching over to elacestrant in a very high-risk population. In Europe, they are doing the TREAT ctDNA, where patients are going along on their adjuvant endocrine therapy, high-risk patients, and they are having monitoring of ctDNA for minimal residual or molecular residual disease, looking for ctDNA relapse, and then randomizing patients to continue their endocrine therapy versus switch over to elacestrant.

In the ADELA trial in Europe, elacestrant and everolimus are being compared to elacestrant. We are going to have combination data as well on everolimus. The ELECTRA trial is combining elacestrant and abemaciclib and looking at brain metastasis. Then I am very interested in this last one, the CAPELA trial, which is evaluating capecitabine plus minus elacestrant after disease progression on a prior CDK4/6 inhibitor. It is a pilot trial randomized phase 2.

We are going to see the phase 3 ELEGANT tips protocol presented. We will see the tips protocol for ADELA here as well, combining with everolimus as well as the ELECTRA trial with abemaciclib and the CAPELA trial in combination with capecitabine. Imlunestrant, we talked about EMBER-3. EMBER-4 is the big adjuvant trial with elacestrant, which has recently completed enrolment.

This is also a switch trial after 2 to 5 years of standard adjuvant endocrine therapy. Now with giredestrant, we have the persevERA trial that we will see the results here at ASCO in the first-line metastatic setting comparing giredestrant palbociclib to AI palbociclib. The pionERA trial is looking at giredestrant versus fulvestrant, both in combination with a CDK4/6 inhibitor, for patients whose disease has recurred on adjuvant endocrine therapy.

Then, of course, the adjuvant lidERA trial that we are very familiar. We saw an update today in the postmenopausal versus premenopausal population with giredestrant. We will see for the first time the data on persevERA on Tuesday, and we saw today the updated data on lidERA by menopausal status. Camizestrant, there is a neoadjuvant phase 2 CERENA-3 trial.

Going on, we await the results of CERENA-4, which is the first-line trial of palbociclib camizestrant versus AI and palbociclib. Hopefully, that will be forthcoming soon. Then the palazestrant the OPERA-2 has moved palazestrant into the first-line setting in combination with ribociclib versus letrozole plus ribociclib. A lot of work going on here, both in ESR1 mutant and ESR1 wild type population.

We will see a trials in progress poster PERA-2 here at ASCO. With vepdegestrant, VERITAC two has reported out there is this first-line trial VERITAC-3 that I believe has been completed. Then there is TACTIVE-U you and TACTIVE-K, which basically are combining vepdegestrant with a variety of other agents, including TACTIVE-K with the CDK4 inhibitor atirmociclib. We will see abstracts on both TACTIVE-U you and TACTIVE-K here at ASCO.

Community Challenge

Let us go back to the community challenge question here. What is the most common or pressing challenge you face when integrating novel agents and applying the latest data on next-generation ER-directed therapies in your clinical practice?

1. Managed care formulary restrictions;
2. Care team unfamiliarity with new agents;
3. Lack of team-based process for AE management with combination therapy; or
4. Difficulty staying current with rapidly evolving clinical trial data.

Please vote.

I can relate to that. It is difficult. We are having so much data and thankfully, so many FDA approvals with more coming this summer. Hopefully, a few more coming this summer.

Identify and Intervene: Developing Best Practices for ESR1 Testing

With that, I think we will transition here to ESR1 mutation testing. I just wanted to see if there were any questions here on our iPad here for a second. Let us see here. Nothing right this minute. Let us go ahead with Michelle. We will talk about ESR1 mutation testing. We will come back.

Dr. Shiller: Thank you so much, everyone. I hope you are really finding this to be a very informative session. Dr. O'Shaughnessy, thank you so much for giving such a wonderful overview of the landscape. It is all so important, and I see these co-mutations in my practice. I really am excited about some of the newer agents because I have also seen those other pathways upregulated and commutated.

It is wonderful to see FGFR covered by one of those agents as well, because FGFR amplification is very common as a resistance we are perceiving and assuming a resistance mechanism in hormone-driven breast cancer. We are going to talk a little more about testing because we have to have a way to identify our patients.

Patient Case 1

That is where I get to have the wonderful opportunity to engage with the clinical colleagues, and really want to reiterate, it really takes a team, all of us working together, communicating, making sure we are getting the patients identified. I really heard that response on a delay in molecular testing results.

I want to understand that better because if we are having a delay there, that means patient treatment care decisions are delayed. That is something I would love to understand for anyone who would like to share that with me ater the talk tonight. We are going to start with this section by talking about a patient case. M.P. is a 60-year-old woman with hormone receptor-positive HER2-negative advanced breast cancer.

She has been receiving an aromatase inhibitor plus CDK4/6 inhibitor. At today's visit, she reports worsening back pain and cough. Current imaging shows multiple lytic thoracic spine lesions and several pulmonary nodules, which I will mention are very difficult to reach by biopsy with disease progression. The oncology team is reviewing the next step in the testing workflow to identify actionable endocrine resistance mutations and support timely treatment selection.

Pretest 3

Which testing approach should the interprofessional team implement at this point?

1. Comprehensive genomic profiling on diagnostic biopsy for a de novo ESR1 mutation; and please log your responses;
2. Comprehensive genomic profiling of the thoracic spine metastasis;
3. Blood-based ctDNA testing using NGS or PCR, or droplet digital PCR; or
4. Defer testing until imaging confirms progression at a biopsy accessible site.

Why ESR1 Testing Matters in HR+/HER2- MBC

We are going to come back to the question at the end after we hear some more data around this. Why is this important? As Dr. O'Shaughnessy indicated, as I let in the importance of biomarker testing in metastatic breast cancer continues to evolve. We see these comutations. We have seen numerous therapies that have been approved in the past few years to harness various alterations in the phosphokinase pathway PIK3CA, AKT, PTEN, as well as for ESR1 mutations, etc.

The guidelines ASCO - NCCN guidelines recommend genomic testing and blood and/or tissue at disease progression to look for acquired mutations. Right now, at disease progression is the recommendation and ctDNA is analysis is likely optimal, as the approach does not require biopsies and can be used to monitor disease progression and detect targetable mutations.

It is common to ask well, what about tissue versus liquid and detection? This is showing some paired sample studies. I call your attention to the differences in, so that orange is going to be where you have concordant negative results. Particularly looking at ESR1 and AKT1, which is a co-mutation pattern that we see.

With the concordant negative, you see that there is a significant number of more concordant negative AKT1 versus ESR1 than concordant positive largest in ESR1. What is really important is when you notice the ESR1, the discordant tissue negative but droplet digital or digital PCR positive. That is on a blood draw. We have quite a few more patients identified through liquid biopsy than through the tumor testing. There could be a multitude of reasons why this is occurring, but it is just important to note that.

ESR1 Mutations: Biology and Clinical Relevance

As we have already talked about, the ESR1 encodes estrogen receptor alpha, and the most clinically relevant resistance mutations are occurring in that ligand-binding domain and can drive ligand-independent estrogen signaling. They commonly emerge after aromatase inhibitor exposure. Typically, they are not de novo in the metastatic setting is where we see them. It can guide the use of oral surgeons' terms, as has been discussed, or other endocrine-based strategies.

NCCN Biomarker-Driven Treatment Recommendations in HR+/HER2- Advanced Breast Cancer

This is a listing of varying biomarker-driven treatment recommendations in advanced breast cancer. We have seen most of these already presented tonight in terms of coverage from therapies.

When to Perform ESR1 Testing

When do we perform the testing? Performing it at progression on endocrine-based therapy and the hormone receptor-positive HER2-negative setting, particularly after exposure to an aromatase inhibitor plus a CDK4/6 inhibitor. I urge you and encourage you, particularly looking at that data for specifically for an ESR1 mutation, to consider blood-based ctDNA testing when tissue biopsy is impractical or when acquired resistance is suspected.

Importantly, if ctDNA is negative and suspicion remains high, it is important to consider tissue testing. If the patient has a lesion that is amenable to biopsy. Also, retesting may be appropriate because it may be negative initially, but this mutation is acquired over time. Repeat testing over time will also potentially be informative.

Testing Methods: NGS vs PCR/ddPCR vs Tissue

Again, prevalence up to 30%, and as time goes by up to 50%. That is one in every three to ultimately one in every two breast cancer patients that you could see this in. The methodology, this is a landscape that remains very diverse and complex at the top, NGS or next-generation sequencing that is our workhorse in the lab.

That is going to give you the broadest look at all of the potential alterations that may be in the patient's circulation. Challenges to that are cost and turnaround time. Again, I am hearing that delay in molecular report, so I want to understand more about that. As well as the one greatest variable we have that is going to impact any of these assays is whether or not the tumor is shedding at the time of the blood draw. Then also it does provide a comprehensive overview at metastatic diagnosis or progression.

With PCR very highly sensitive, and PCR, typically, the way to think about PCR is you are going to get an answer to the question which you ask. If you are using that it is important to know the coverage of the assay specifically. It might be a good use case for serial monitoring in terms of cost control, once what you are trying to track.

It is limited, like I said, to predefined mutations. For novel mutation identification, NGS would be a better option, and focused ESR1 testing for tracking known mutations would be a good use case for that. Tissue testing again, not to forget that we have that to fall back on when plasma ctDNA is negative or non-informative, when there is a biopsy site that can lead to testing. It does require biopsy and may miss tumor heterogeneity that is reflected in the circulation. It can be implemented as reflex testing or when clinically needed

ctDNA Testing Approaches for ESR1 Mutation Detection

Then, looking at the approach, how do we first try to find these mutations? One thought is to start with a comprehensive genomic profiling or ctDNA panel. Right now, there are not sweeping recommendations on this per se. That will detect your ESR1 alteration, but it could also detect any mutations which we saw the outcomes for patients with a PIK3, a mutation in particular, they do not have that benefit as some of the other.

It is just important to know what else is going on with this tumor, and especially as therapeutic options continue to emerge. The thing to think about is it does come at a higher cost. It is also going to have a longer lag in the turnaround time, just due to that informatics component. When we are trying to analyze the data.

A potential reimbursement barriers and then feasibility concerns for serial monitoring likely and largely also contributed to those reimbursement considerations. Another thought would be a smaller, targeted ctDNA panel. It would be more focused and maybe more practical for repeat testing.

Maybe the savvy panels might have some of those co-mutation patterns that we are already seeing, such as PIK3CA, TP53, etc. Then, if you are doing a panel, it is going to miss any alterations that are not covered by that panel. The availability of those varies. Then another approach could be single gene ESR1 testing that could be potentially similar and lower cost.

It might be a good option for known monitoring. Once you have identified the patient and that assay does cover that mutation to serially monitor the patient to determine whether or not that value is lowering in response to therapy, and at which point it might be rising again to start suggesting possible emergence of a new resistant clone. It may not provide your broader genomic context, and the availability and validation may vary. In the SERENA-6 trial, which Dr. O'Shaughnessy mentioned, they used a comprehensive profiling ctDNA assay.

PADA-1: Palbociclib + Fulvestrant vs Palbociclib + AI in Patients With Rising ESR1m After Palbociclib + AI

There have been multiple trials looking at this. I am really here just to highlight that this is ongoing and clinical investigation. One of the first ones to look at ESRI in the circulation was the PADA-1 trial.

SERENA-6: CDK4/6i + Camizestrant or AI in ESR1m HR+/HER2- MBC in Patients Without PD on 1L CDK4/6i + AI

Then SERENA-6 is the one that is currently in active review by the FDA. We are still waiting to see what that outcome will be.

TREAT ctDNA: Elacestrant for ER+/​HER2- BC With ctDNA Relapse

Then also, as Dr. O'Shaughnessy mentioned, the TREAT ctDNA, which is in Europe and they are looking and monitoring the patients and giving therapy if there is no evidence of distant metastasis or locoregional recurrence. That is ongoing.

Implementing ESR1 Mutation Testing in Community Practice

How do we implement this in community practice? Weighing the pros and the cons, what are the things that are in favor? It is minimally invasive. It may reduce the need for repeat more invasive tissue biopsies. It also might be easier to repeat over time, and may help to also detect acquired resistance mutations depending on your testing approach, broad versus focused, etc.

It may provide insight into molecular disease evolution as well as to help inform future approaches for treatment selection, keeping options on the table for the patient. Some of the challenges we always face this in the laboratory is the detection of the ESR1 alteration below the limit of detection.

When we are in this space, it is important to understand what the limit of detection was in the clinical trials so that you know what the threshold was that was reported out, and if that test that you are using is lower than that, then you can already know that in the investigational setting, that actually was not studied.

We do not really understand or know fully yet what that means, but just understanding the limit of detection of the assays. Insurance coverage and prior authorization is going to be another thing we have to think about that will also come into play with the size of the panel you are using.

If you use a panel and help you to think about sequencing, testing, maybe starting with a big question, then going more focused. Then, if you start seeing that focus target rise, go back to the big question, something along that. We are still all learning. That is part of that multidisciplinary component here. The turnaround time, and when you guys get the results, tracking serial testing intervals, interpreting negative or low shedding results, and then patient education and anxiety around molecular progression.

What to Expect: Interpreting ESR1 Reports

Here is a sample report. It should describe what it is that we did. What type of sample we used? Plasma or tissue. What we detected and at what rate the variant allele frequency. Other alterations, limitations of the test, which actually become very important in some settings, as to what did the test not interrogate and the clinical correlation of the result.

When to Consult Pathology in ESR1 Mutation Testing

When to consult pathology. When our test details are unclear, and I hope that is very infrequent because you guys do not need to be chasing us down. When you need advice on what specimen type to use or which specimen to submit. What assay or method approach, you should consider coverage of the assay mutation coverage.

When the plasma ctDNA is negative or non-informative to assess for low shedding disease and refluxing to tissue. If the result is difficult to interpret because there is an uncommon variant or a low variant allele frequency, maybe it is just right on that cut-off or other limitations of the assay that it might be bumping up against.

When the clinical findings and the molecular results do not align. That is again, why pathology should really be engaged with this testing so that we know and make sure everything is cogent with the testing, and tissue testing is needed to see if it is needed, selecting the best specimen, and confirming adequacy of tumor present.

Example ctDNA Detection Test Result

Here is another example of a ctDNA detection result. At the top, you can see that there was an ESR1 mutation detected. Then, in this potential therapeutic options section, this patient had an ARID1A mutation as well detected in the circulation under other oncogenic variants. You see a few probable chip alterations, clonal hematopoiesis of indeterminate potential, and pertinent negatives on the right-hand side. Always important to know what other things the assay asks that may relate to that patient.

Posttest 3

Following up on the question, which testing approach should the interprofessional team implement at this point?

1. Comprehensive genomic profiling on the diagnostic biopsy for a de novo ESR1 mutation;
2. Comprehensive genomic profiling of the thoracic spine metastasis;
3. Blood-based ctDNA testing using NGS or PCR droplet digital PCR; or
4. Defer testing until imaging confirms progression at a biopsy accessible site.

Please answer.

Most of the answers came in with the blood-based testing. The comprehensive profiling on the diagnostic biopsy, this is a patient at progression, and the de novo ESR1 mutation is very uncommon, so at less than 1%.

That is the reason why that is the right answer. The comprehensive genomic profiling of the thoracic spine metastasis. Typically, we cannot test bony metastases due to decalcification. No one picked that or D the defer testing until imaging progression.

Community Challenge

Here is another community challenge question. What is the most common or pressing challenge you face in practicing regarding ESR1 testing?

1. Insurance restrictions on testing;
2. Reliance on off-site pathology;
3. Delays in result reporting; or
4. Unclear result reporting.

Please answer.

This is also very insightful for me as a pathologist. The reliance on off-site pathology, as well as unclear result reporting. As a pathologist, I will take that back to my pathology colleagues. I also encourage you to share more with me at the end of the talk.

Discussion: Overcoming Barriers to ESR1 Testing in Clinical Practice

I am going to go ahead and hand it off to Dr. Mardones.

Dr. O'Shaughnessy: Thank you very much. Michelle, I have some questions for you, but we will wait until I think until after Mabel.

Maximizing Therapeutic Benefit From
Next-Generation ER-Directed Therapies: Interdisciplinary Approaches to Managing AEs and Supporting Adherence/Persistence

Dr. Mardones: I am going to bring us home by discussing AEs. At the end of the day, this is all the practical things that we need to understand. People cannot benefit from drugs if they can either not tolerate it or we as physicians do not feel comfortable. That is the whole entire team, APPs included.

Patient Case 2

Let us start with a case. This is a 62-year-old postmenopausal woman. She is ER positive, HER2 negative advanced breast cancer. She has bone and liver metastases. She received first-line endocrine therapy, letrozole with ribociclib, with disease control for 18 months. She now has radiographic progression in the liver but remains asymptomatic. CtDNA assay identifies an ESR1 mutation, with germline testing being negative for BRCA1 and 2. The tumor does not reveal a currently actionable PIK3CA, AKT, or PTEN alteration.

Pretest 4

The patient's care team is planning on initiating elacestrant as monotherapy. What is important to consider when starting therapy with elacestrant? These are the following answers.

1. Is obtaining a baseline lipid function test. Review medications for CYP3CA interactions;
2. Arrange ECG monitoring and ophthalmologic examination or evaluation, and review medications for CYP3A interactions;
3. Perform tissue-based testing to confirm the lack of PIK3CA AKT PTEN alteration; or finally
4. Consider adding abemaciclib given liver metastases.

Please vote.

50% voted perform tissue-based testing to confirm the lack of PIK3CA. Another 25% said ECG monitoring with an Ophthalmologic evaluation, 12% picked lipid function testing and review of CYP3C interactions, and the other 12% considered adding abemaciclib. We are going to go back to that case after this discussion.

Patient Case 3

Another case. We have a 62-year-old postmenopausal woman now. She is ER-positive, HER2-negative. She has ESR1 known mutated advanced breast cancer that started on imlunestrant 400 mg daily after progression on prior endocrine therapy. At a routine follow-up visit after four weeks, she feels well, denies abdominal pain, no jaundice, no dark urine, nausea, or fatigue.

However, in the laboratory testing, we show an AST four times the upper limit of normal, ALT 4.6 times the upper limit of normal, with a normal bilirubin, important to note. Baseline AST and ALT were within normal range when you started the patient on imlunestrant. Repeat testing confirms persistent grade 2 transaminitis elevation.

Pretest 5

What would you recommend for this patient?

1. Would you continue at the current dose and recheck liver test at the next routine, visit;
2. Hold until AST and ALT improve to baseline or less than three times the upper limit of normal, then resume at the same dose;
3. Hold until AST alt normalize, then resume at a reduced dose of 200 mg daily; or
4. Permanently discontinue because any persistent AST and ALT elevation requires discontinuation.

Please vote.

Two popular answers. Nearly 70% said hold until AST, ALT normalize, then resume at a dose reduction, and the other 33% voted to just hold until baseline, return to normal less than three hours, and then resume at the same dose. We will review topics and following.

Safety of Oral Next-Generation ER-Directed Therapies

These are the landscape of current AEs that are most common, starting with the orange GI issues namely, are the most common nausea, vomiting diarrhea. Less common AEs included with SERDs are bradycardia, most typically grade 1. Then we also have QTc prolongation. We will talk about that. Visual disturbances fatigue with almost all oral agents, and then, particularly related to endocrine suppression, are hot flashes and arthralgias, particularly with AIs.

Approved Oral Next-Generation ER-Directed Therapies: Overview

With both EMERALD and EMBER-3, you see here the dosing are 345 mg daily with food, important to note. With imlunestrant the starting dose is 400 mg daily on an empty stomach. Then with vepdegestrant, that is 200 mg daily, starting with food. This cannot be underscored. This is why pharmacists are critical in our practices.

That is CYP3C substrate inhibition or P-gp inhibitors. Importantly, to note with vepdeg is that you have to have an acid environment in order to absorb the agent, and therefore not being on a PPI or even an H2 inhibitor is very important. Those are very prevalent in our practice. That is very important to note.

When it comes to renal adjustments, hepatic dosing adjustments none are necessary with elacestrant. It is really unclear with imlunestrant and vepdeg as to whether those need to be modified at all. Then at the bottom, hepatic adjustments are not recommended when one has a Child-Pugh a, but Tell to be with elacestrant. That has to be reduced to start. As you see, with Child-Pugh, B and C, initial reductions with imlunestrant are necessary, and then mild hepatic impairment. No adjustments necessary with vepdeg as you see there.

ELEVATE: Elacestrant Combinations in ER+/HER2- ABC

This is ELEVATE. This is a trial that we will have some updates in following here at ASCO. This is looking at elacestrant in combination with various other agents, including other CDK4/6 inhibitors. At this meeting in particular, we are going to hear about the combination of elacestrant and capivasertib, at this meeting as you see there on June 1st.

EMBER-3 Update: Safety Summary

With EMBER-3, as you noted, it is really nice to see when grade 3 toxicities are all below 5% as you see there. Draw your attention to particularly GI issues here with diarrhea. As expected, when you combine imlunestrant with abemaciclib, you are going to have higher incidence of cytopenias and higher incidences of GI toxicity. Overall, important to note that discontinuation rates by far, even in the combination or as monotherapy, were very low, 5% and with a combination 9%.

VERITAC-2: Safety Summary

How about vepdeg, our new indication? Here we see what I think is notable to note which is fatigue is different than fulvestrant. AST ALT can be elevated as well. Then this is the agent that we do have to be very careful with QTc prolongation. All grade toxicity when it came to QTc is around 20%, but grade 3 events were less than 3%. Importantly, as all is important to note on all of these trials, treatment discontinuation was exceedingly low. Extremely well-tolerated agent by and large.

Safety Summary of Oral Next-Generation ER-Directed Therapies

This is a summary. This goes back to our question, which is elacestrant; we do have to be careful about 33% of these patients did have elevated cholesterol and triglycerides. That is a requirement to at least note at the beginning before you start a patient. Gi toxicity is uncommon, but it is one of the things we need to watch out for.

With imlunestrant the GI toxicities, of note. Triglycerides and hypercholesterolemia are not uncommon, but less so than with elacestrant. With vepdeg as I noted, it is important to have a baseline EKG due to QT prolongation that is noted. Then we will talk about the recommendations on dose reductions.

With camizestrant, we do see some bradycardia, but by far all of these events are grade 1, so asymptomatic. There are noted cases of photopsia or vision flashes of light that are not disturbing to patients. That is something to note. With giredestrant, sinus bradycardia. All grade toxicity is about 11%, grade 3 less than 3% with that agent.

Elacestrant Dose Modification Recommendations for AEs

These are generally the recommendations for dose reductions. If someone has a grade 2 toxicity is recommended that you stop and hold the agent and then resume at the same dose for those patients. If their grade three toxicity, then you withhold until resolution, and then you lower the dose.

If it is a more severe grade 3 event. Then of course, if you withhold to less than but it resumes again or it recurs, then you really should permanently discontinue the agent. As you see there, these are the dose reductions. There are three starting with 345. The next are three tablets at 86 mg. Then the final dose reduction is two tablets at 86 mg.

Imlunestrant Dose Modification Recommendations for AEs

These are dose modifications for imlunestrant, fairly similar concepts outside of hepatotoxicity. If grade 2 event you are going to hold until resolution and then resume at the same dose. If a grade 3 or 4 event, you have to do a dose reduction. Now, when it comes to hepatotoxicity in particular, again, going back to our question, I think this particular case had bilirubin was normal in that case, but their AST ALT was 2 to 4.6 times the upper limit of normal.

They really fell into that category where you can hold and resume at the same dose. If someone has obviously severe AST ALT elevations 20 times the upper limit of normal, you have to permanently discontinue. Then you really have to watch for that bilirubin. That is a higher grade toxicity when it comes to your liver.

Vepdegestrant Dose Modification Recommendations for AEs

Then speaking about vepdeg, since we are all getting familiar with this agent and thinking about use the recommended is if grade 1, you continue treatment without dose adjustment. If they have grade 2 toxicity, then you drop the hold and then resume the dose at 200 mg. Very similar concepts to what I have already mentioned, but these are not specific to QTc prolongation.

Vepdegestrant Dose Modification Recommendations for QTc Prolongation

Let us talk about QTc in particular. We do have to have an EKG up front. If their QTc is greater than 480 ms, then it really is recommended that you do not start and you figure out whether the patient has a reversible cause. Checking for hypokalemia or hypomagnesemia is very important. If their QTc is greater than 500 ms, you have to hold until the QTc resolves to less than 480 or less than 60 ms above their baseline. Then you do have to check their QTc more frequently. Obviously, if a patient develops any symptomatic ventricular tachycardia of any sort, then you do have to permanently discontinue this agent.

Balancing Quantity and Quality of Life

Like anything, if we want to maintain this very delicate balance of quality of life and keep patients with the best optimal, you have to keep and persistently on these medicines. The best thing that we can do for these patients is help them understand their adverse events. They have to have a positive view of these medications. Overall, a positive relationship with their physician and their care team. We have to effectively manage their symptoms, and they have to be satisfied with their follow-up care and emotional support in their home is obviously very important.

Counseling Points for FDA-Approved Oral Next-Generation ER-Directed Therapies

Just to summarize, elacestrant and vepdeg are to be taken with food, imlunestrant on an empty stomach at least two hours before and an hour after food. Swallow the tablets whole. Do not cut any of the tablets. If there is a missed dose for six hours or more, do not take an additional dose and then resume at their regular scheduled time.

Start these patients, particularly if they are going to be doing elacestrant and imlunestrant, and have them have oral antiemetics at their disposal. Obviously, reporting any unusual cardiac symptoms, particularly with vepdeg as we discussed, and keeping in line with your ECG and follow-ups. Then, importantly, women who are of childbearing age should remain on effective contraception when using all of these agents.

Optimizing Patient Education and Adherence

There is a handy teaching tool here for both your patients and for physicians. At the bottom, as you see there, these are some of the things that we should consider in our clinics, assessing the readiness of those patients to receive information, ensuring a caregiver's presence so they too can hear some of the toxicities.

Often, these patients are overwhelmed. Often, they progressed. They are often not paying attention at that very first meeting, so having someone else an extra pair of ears, setting expectations, right duration, pill burden, prevalence of ease and outcomes, delivering written information for these patients.

Super important. Providing trustworthy, reliable information in writing if possible, identifying gaps in education, walking through financial concerns. These drugs are not inexpensive. Oftentimes, our patients ask us, is this a drug that I can afford? We often do not know that. That leads exactly to the next point, which is not only drug-drug interactions matter, but our pharmacists and having contact and visibility so that people can access information not only in our own clinics, but through pharmacies, is super important. We would like to know what you guys are doing in your own practices and encouraging support groups like support groups that that truly are educational overall.

Oral Targeted Therapy Adherence Considerations

Then this is a summary of what I have just said. Particularly, honing in on drug-drug interactions and knowing what our patients are taking. Oftentimes, it is easily missed in our clinic. We are not updating what other, what folks are doing. Increasingly more common is the use of supplements in our clinic. That is truly important to also have us be engaged with. Hopefully, our patients are forthcoming about that. Again, that is all going back to trust.

Posttest 4

Let us review here our post-testing questions. This was the question about initiating elacestrant as monotherapy. What would you consider upfront, now that we have reviewed everything? Please vote. I expect 100%.

We were supposed to have 100% on the first one. This is our drug that we do have to monitor for not only liver, but cholesterol and drug-drug interactions, so remember that. It is that top green there.

This is not the one that - camizestrant is the one that has the photopsia issues, and let us go to the next one.

Posttest 5

This is the patient who was had an ESR1 mutation had started in imlunestrant at 400 mg daily and had her liver enzyme elevation. Please vote again.

We have definitely learned here. Pretest was 33%. We are now at 50%. That is the correct answer, because she did not have a bilirubin elevation. It was not a sufficiently high enough upper limit of normal. We can resume, hold, and resume at the same dose.

There is the rationale.

Community Challenge

Community challenge question. What is the most common or pressing challenge that you face in practice regarding AE management and medication adherence?

1. Is staff and resource constraints from AE monitoring;
2. Follow-ups limited access to specialists;
3. Patient reluctance to continue therapy due to tolerability issues; and finally
4. Patient comorbidities.

Please vote.

Pretty a majority here with patient reluctance to continue therapy due to tolerability. That is very interesting, and it definitely resonates with me, and you see a display of the other options as well there.

Please do not forget the QR code. You can download this presentation.

Poll 3

Importantly, we want to do one final polling question, and then we will get to our Q&A. Do you plan to make any changes in your clinical practice based on what you have learned on today's program?

Poll 4

Then, finally, please take a moment to enter one key change that you plan to make in your clinical practice based on tonight's education.

Q&A

With that, we will go to Q&A.

Dr. O'Shaughnessy: Thank you very much. That was a very great review. It is good. The agents are coming so fast and furious. It is very important to have that review and get that into the head here, with or without food, the PPI, the liver, etc. Thanks very much for that very clear discussion. We have had multiple questions come in here for us to discuss, and the few minutes that we have.

One question relates to testing, and that is somebody on the AI CDK, and now they have clearly progressed, and you get the ctDNA, and there is not an ESRI, and there is not anything else to go after either. What is the best strategy? Do you just start the next empiric treatment? Do you consider a biopsy of a metastatic lesion for NGS? Do you go back to the original primary breast cancer MGUS? What do you think, Michelle?

Dr. Shiller: There are a few thoughts. One is, as you said, you were saying there was nothing else detected at all. I just want to make sure that the test did cover things beyond ESR1. Just looking at did the test, ask a big question, and look at lots of genes or just the one, because that would be one reason why it might be negative, is a different mutation.

Then I think there is not a recommendation at this time as to the cadence as to the follow-up. I think it would be your clinical impression if you are trying to find it on circulation. If the patient has a lesion that you can biopsy, I would encourage you to try to get the biopsy if the patient will agree to it. Testing the treatment naive tumor, I would be concerned that would not be as helpful because you have put a selective pressure on those cells. Last resort, maybe do that, but preferably something that is going to be more time sensitive to that patient right now.

Dr. O'Shaughnessy: Thank you. Then we generally would repeat ctDNA testing again at progression, probably. I would not necessarily redo it with another lab or anything - I have not. Have you found much variation? If you got negative on the ESR1 and no targets, and you go to another lab, Michelle, are we likely to find anything, or not particularly or?

Dr. Shiller: It could depend on the lab. It is going to depend on the sensitivity of the assay. Also, we are dependent upon whether or not the tumor is shedding. That is always the question mark when we are dealing with the liquid versus tumor, because if we have the tissue, we know what we have put in, whether or not the quality of the DNA, which hopefully the links have been sorted because of the regulations from the CAP with tissue, but with a blood draw, we do not know.

We cannot look and say, "Oh yes, we have a lot of tumor DNA." I do not believe that the variability would be dependent, per se, on the laboratory, though there are going to be varying sensitivities. That is an important question to ask with any laboratory that you choose to test with is how sensitive is it?

Like I said, importantly, what was that threshold that was used in the clinical trial, and are they at least detecting at that or maybe even lower? Whether or not that would inform a clinical change is to be determined, but still, to make sure they are at least reaching that threshold.

Dr. O'Shaughnessy: As you choose among the various options, because there are a number of options out there these days. Just one more testing question. Sometimes, very often, particularly as patients progress through their natural history, there is multiple mutations. We are trying to decide is it the ESR1. Is it the PIK3CA and variant allele fraction? She knew this was going to come up here. Does it matter that one static moment in time? Does it matter if you happen to be monitoring it serially, and one is going up more than the others, etc.?

Dr. Shiller: The variant allele fraction does imply how much of the particular mutation you are seeing. I think classically, we thought what you see the most is what is driving the disease, but as you are suggesting, say you have ESR1, and you have an AKT, and at first testing, you have 0.6% ESR1, and you have 0.05 of AKT1.

Then you retest and that ESR1, let us just say it is 0.65 for the purposes of illustration. Then AKT1 is now 0.3. That is a significant growth. That tells you that phospho kinase pathway is being upregulated. We need to start harnessing that because likely that AKT1 is going to catch up. Now you should always detect that initial resistance clone, but the other one is likely to overtake it. We are still learning, but that is what I would expect.

Dr. O'Shaughnessy: Dynamics is important, basically. Very much so.

Dr. Mardones: I would like - to ask about proteomics, and where do you think that would be, because it makes me think about-

Dr. O'Shaughnessy: Proteomics?

Dr. Mardones: Yes.

Dr. O'Shaughnessy: Like you are doing tissue and then doing proteomics on tissue to see if a pathway is really active.

Dr. Shiller: I think that that is actually a wonderful adjunct, especially not tonight's topic, but looking at multi-cancer early detection, really, the cat's meow there is combining all of our different abilities to really understand and inform what is going on. Yes, multiple different approaches is always going to help us to know that alteration, is it actually impacting the function, the ultimate protein function?

Dr. O'Shaughnessy: Mabel, one of the questions that came in is not the easiest question in the world, but because a lot of these agents are new to us, and that is how do we choose now post CDK4/6 plus AI, elacestrant, imlunestrant, and vepdeg if we have got an ESR1 mutation. vepdeg is so new, we have not had a chance outside of trials to use it yet.

We have only had imlunestrant a few months, so it is still very early. We have had quite a bit of experience with elacestrant, but just talk about your experience with elacestrant so far. Where have you seen a benefit where not? How might you use imlunestrant at this point? What are you thinking about vepdeg?

Dr. Mardones: When you do not have head-to-head comparisons, which we do not, I think we are left with what resonates with me is the CDK discussion. For a long time, we said what is better? Is it ribo? Is it abema? I think we are now in that space and the second-line setting. Now, I think like everything, we are more familiar with elacestrant, and that is probably a familiarity component when it comes to AEs that makes everyone feel more comfortable.

 That said, I have enrolled patients in the imlunestrant. I have been extremely impressed, not only with the tolerance there. I have had patients who do not tolerate elacestrant, right, who are in the minority, who just do not do well from a GI perspective. It is beautiful to have another drug that I can switch them to.

With vepdeg, I have experience in clinical trials, but I would not say there is huge differentiating ways that I would say it is just what you have available, the side effect profile, maybe drug-drug interactions, and things of that nature will have to weigh into these discussions. Then by the end of the year, we might have as well - and so we have four things to consider. How about you?

Dr. O'Shaughnessy: Like everybody imlunestrant I have been using, of course. I have had occasion recently myself, and then I have an anecdote or a patient case, I should say, from a colleague of imlunestrant benefiting my patient and her patient after progression on elacestrant. We have a lot to learn about these various mutations and what subclones are coming up, etc.

I have an older gal who did well on elacestrant for 9, 10 months, bone only progression 74. She is very toxicity adverse. I gave her imlunestrant and she is had a very nice response. I have heard of another such case as well. I am really going to be interested in seeing if we can parse out. It seems like there is differences among these agents. Maybe we are going to get some non-cross resistance with serial use.

I will predict that in the context of ESR1 mutations, we are going to always want to have that thing blocked when we are doing endocrine therapy, not with chemotherapy, but endocrine therapy. We are going to - either monotherapy or in combination, then we are not going to be satisfied going back to a fulvestrant.

For example, we are going to use these serially generally in combination sometimes in monotherapy, but we will have an opportunity to use multiple of these over the natural history of patient's disease, I suspect so. Good times because these PFS are getting up there with monotherapy, six to nine months, and combination therapy exceeding that. It is good. Very good new tool.