A couple of other considerations in advanced breast cancer.

[00:45:53]

Patient Case 3: Metastatic Recurrence While Receiving Adjuvant ET

Let us start with a case here. This is a 57-year-old postmenopausal woman who had high-risk node-positive early breast cancer in 2021. She got adjuvant chemotherapy radiation, was started on adjuvant letrozole. She also was started on adjuvant abemaciclib but she did not tolerate it so she stopped after only 6 months of treatment. Now she comes in 3 years later, 2025, with fatigue, weight loss, and essentially is found to have metastatic disease with a burden in her bone, liver, lymph nodes. It is confirmed ER 50%, PR 30%, and HER2 negative or 1+. She is found to have an ESR1 mutation based on ctDNA evaluation and she is found to have a PIK3CA mutation.

[00:46:49]

Posttest 4

Now, what would you use in the first-line setting for this patient? Remember she recurred a couple of years out on her AI alone in the first-line setting she had. Now you are selecting first-line treatment and she has a dual mutation ESR1, PIK3CA. Are you going to treat her in the first line with:

1. Capecitabine;
2. Elacestrant;
3. Fulvestrant and a CDK4/6 inhibitor;
4. Fulvestrant and a PI3 kinase inhibitor; or
5. The recently approved triplet combination of fulvestrant, palbo, and the PI3 kinase inhibitor inavolisib.

Please choose.

Speaker: Polling is open. Please vote. We will allow a few more seconds. We will go ahead and close the poll.

Dr Iyengar: Okay. I have got a bit of a distribution here, but looks like majority 39% are voting for fulvestrant and a PI3 kinase inhibitor, and then we have got the triplet combination coming in next, fulvestrant, palbo, and inavolisib in the first-line setting.

[00:48:07]

ER/PgR+, HER2- MBC

All right. Let us just go through the data here to address that case here. Here is the treatment algorithm for hormone receptor positive, HER2-negative metastatic breast cancer. You can see there that it is really divided up into endocrine therapy response. If the patient experienced a recurrence that was greater than a year, 12 months after completing their adjuvant AI or no previous AI exposure, then in the first-line setting, certainly consideration of an AI plus CDK4/6 inhibitor. Now, if they have a recurrence while they are on their adjuvant AI or within a year of their adjuvant AI, this is where you would use fulvestrant instead of an AI, fulvestrant plus a CDK4/6 inhibitor. Now moving into the next lines at progression, certainly want to do tumor genomic profiling again. Here you can see it is a biomarker-driven approach with elacestrant as an option for those who have an ESR1 mutation, fulvestrant capi for those who have a PIK3CA, AKT, or PTEN alteration. If they only have a PIK3CA alteration and they have not gotten fulvestrant in the past, you can consider alpelisib or capivasertib with fulvestrant. If there is no actionable mutation, exemestane, everolimus is an option or tamoxifen monotherapy is an option as well.

[00:49:34]

Summary Data for First-line Combinations of CDK4/6 Inhibitors and ET in HR+/HER2-Breast Cancer: PFS and OS

This is really summarizing the first line CDK4/6 inhibitor trials. I will not belabor it here. But certainly in the metastatic setting, we have the option of 3 different CDK4/6 inhibitors, palbo, ribo, or abemaciclib, noting that for ribociclib we have 3 trials MONALEESA-2, -3 and -7, which tested either letrozole or fulvestrant, and specifically a trial that was dedicated to premenopausal patients here. If you look down at median PFS, you can see that median PFS was pretty similar across the trials there, ranging from 20 to nearly 30 months. OS is where we start to see some differences here, with statistically significant overall survival benefits noted in the 3 ribociclib trials, but not quite reached in MONARCH-3 and not reached in PALOMA-2, the palbociclib and abemaciclib arms.

[00:50:40]

Additional Phase II/III Trials of First-line Combinations of CDK4/6 Inhibitors and ET in HR+/HER2- Breast Cancer

Now, there have been several additional trials here that I think are worth mentioning here. The RIGHT Choice trial is important to keep in mind here because this really looked at a high-risk, high-burden population whom you might actually consider chemotherapy for. This trial randomized patients with aggressive or high-burden disease in the first line to get ribo, anastrozole with ovarian suppression, or letrozole if they were postmenopausal, vs investigator’s choice chemotherapy. What you can see here is that median progression-free survival favored the ribociclib-containing arm over chemotherapy, indicating here activity even in our high-burden disease burdens patients that CDK4/6 inhibitor is an option there. SONIA was a trial that looked at de-escalation here and there. They looked at basically introducing the CDK4/6 inhibitor in a subsequent line there and essentially showed similar PFS2s. But I think the problem here is that we do not have a good biomarker for identifying those patients who may not need a CDK4/6 inhibitor in the first-line setting and, given the overall survival benefit of ribociclib, I would find it difficult to not use a CDK4/6 inhibitor in the first-line setting. Then finally PARSIFAL-LONG, which was testing palbociclib plus fulvestrant vs palbo plus letrozole. I think the major take-home point here, interestingly, is looking at that median PFS is really quite extended whether you use fulvestrant or letrozole with palbociclib, and also looking at that median overall survival. Those numbers—68.5 months, 61.9 months with palbociclib—are interestingly similar to the OS numbers that were seen in the phase III trials for the other 2 CDK4/6 inhibitors, although, noting that PALOMA, the phase III trial of palbociclib, did not show an OS benefit with palbociclib in the first-line setting.

[00:53:11]

Patient Case 4: Elevated LFT With Ribociclib

That was a bit of a whirlwind, but let us apply it here. This is a patient who is on ribociclib and experiencing elevated LFTs. She is 55. She has disease recurrence 3 years after completing her adjuvant endocrine therapy, asymptomatic bone-only disease. Started on first line letrozole ribociclib. But now at cycle 2, Day 1, you see her LFTs are 5 times the upper limit of normal, which is a grade 3 hepatotoxicity. She is asymptomatic and EKG is stable.

[00:53:46]

Poll 2

How would you manage the grade 3 LFT elevation? Would you:

1. Continue ribo same dose;
2. Continue ribo but dose reduced to 400;
3. Hold it until it resolves and restart at the same dose;
4. Hold it and instituted a dose reduction; or
5. Discontinue ribo.

Speaker: Polling is open. Please vote. A few more seconds for incoming responses. We will go ahead and close the poll and share.

Dr Iyengar: Okay. Option D there got 58% of the votes, that is hold the ribo and institute a dose reduction. That is essentially correct here.

[00:54:41]

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention to Maximize Adherence

This is a summary slide of how to manage and monitor AEs associated with the various CDK4/6 inhibitors. Here I reviewed abemaciclib and ribo in the adjuvant setting. Pretty similar here, just noting that the dose of ribo is a bit higher here in the metastatic setting. But certainly, management and treatment approach is essentially the same. Just noting that there is a small risk of venous thromboembolism with abemaciclib, so keep that in mind for your symptomatic patients. Then there is a small risk of ILD as well across this class of drugs, so also something to keep in mind if your patient develops new hypoxia or cough.

[00:55:24]

Monitoring and Management of Ribociclib-Induced Hepatotoxicity in Advanced Breast Cancer

This is the algorithm for managing ribociclib-induced hepatotoxicity. Our case kind of alluded to this. If you’re grade 3, that is 5 to 20 times the upper limit of normal, you do want to hold and then dose reduce. If you are 3 to 5, the upper limit of normal, that is grade 2, you can hold and then resume at the same dose. If you are up to 3 times the upper limit of a normal, no changes are needed.

[00:55:55]

ER/PgR+, HER2- MBC

This is again the summary of the treatment algorithm in this approach here. I just want to point out here that for our highest-risk patients who reoccur on their adjuvant AI, or within a year of completing their adjuvant AI, who also have a PIK3CA mutation, we now have the triplet therapy inavolisib plus palbociclib plus fulvestrant as an approved option based on results from the INAVO120 trial, which showed a significant PFS benefit for using that triplet combination, a median PFS of 15 months in the inavolisib arm vs 7.3 months in CDK4/6 inhibitor plus fulvestrant arm here. Certainly, a benefit there, leading to the FDA approval . . .

[00:56:39]

INAVO120: Inavolisib + Palbociclib + Fulvestrant for PIK3CA-Mutated, Recurrent MBC

. . . again, for patients with the PIK3CA mutation who recurred on or within a year after their adjuvant endocrine therapy.

[00:56:49]

INAVO120: PFS by Subgroups

I am just going to move forward in the interest of time here, because I also want to point out here the PADMA trial, which was similar to the RIGHT Choice trial testing, endocrine therapy plus palbo vs standard chemotherapy in our high-risk patients here, our high-burden patients there.

[00:57:08]

PADMA: Baseline Characteristics

I will just point out here, if we look at our time to failure rate here, this favors the palbociclib arm here, again, indicating that for our high-risk, high-burden patients, CDK4/6 inhibitors are indeed an option here.

[00:57:27]

Guidelines for Biomarker Testing and Targeted Therapies in Breast Cancer

Orr the second-line treatment, and we have only got a few minutes left here, so I just want to point out that, again, this is a biomarker-driven approach that I summarized earlier. If you see an ESR1 mutation, elacestrant is an option. PIK3 or AKT pathway alterations, capivasertib is an option. If it is just a pick 3 CA, you also have the option of choosing alpelisib, although we know that alpelisib is associated with significant toxicities here.

[00:57:54]

CAPItello-291: Investigator-Assessed PFS of Fulvestrant + Capivasertib or Pbo in AI-Resistant, HR+/HER2- ABC

These are data for capivasertib from the CAPItello-291 trial, which led to the approval of capivasertib plus fulvestrant because of that PFS benefit in patients with PIK3CA or AKT pathway alterations here, although overall survival did not quite cross the statistically significant mark. But we did see a PFS benefit for capivasertib, the AKT inhibitor in patients with AKT or PIK3 kinase pathway alterations here.

[00:58:30]

SOLAR-1: Investigator-Assessed PFS of Fulvestrant + Alpelisib or Pbo in AI-Resistant, HR+/HER2- ABC

The SOLAR-1 trial was the data that led to the registration of alpelisib as an option for patients with PIK3CA mutations. Again, no overall survival benefits seen with alpelisib, but a PFS benefit is what prompted the FDA approval there.

[00:58:47]

Key AEs With PIK3CA Inhibitors: Monitoring and Prevent to Maximize Adherence

We know that these agents are all associated with toxicities, namely hyperglycemia, both inavo and alpelisib, with the highest rates of hyperglycemia. Capivasertib with some but significantly less hyperglycemia.

[00:59:02]

ESR1 Mutation Is Associated With Poorer Prognoses

I would be remiss not to mention oral certs for patients who have ESR1 mutations here.

[00:59:08]

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

The EMERALD trial led to the approval of elacestrant monotherapy based on benefit for patients with metastatic disease and an ESR1 mutation.

[00:59:19]

SERENA-6: Camizestrant vs AI With Continued CDK4/6 Inhibitor in ER+/HER2- Adv BC

Most recently, we have seen data from the SERENA-6 trial, which used a ctDNA testing approach and essentially randomized patients to continue their AI plus CDK4/6 inhibitors upon emergence of an ISR1 mutation or the switch treatment in the absence of radiographic progression, but a new ESR1 or an ESR1 mutation on ctDNA testing. They were switched to camizestrant as their endocrine therapy and oral surgery while continuing the CDK4/6 inhibitor and the AI.

[00:59:55]

SERENA-6: PFS

This approach demonstrated a PFS benefit there, with a median PFS benefit of 16 months in the switch-to-camizestrant arm vs 9.2 months if you continued standard first-line therapy upon detection of an ESR1 mutation.

[01:00:12]

Let’s Revisit Our Cases

Okay. Let us go back to the case here.

[01:00:15]

Patient Case 3: Metastatic Recurrence While Receiving Adjuvant ET

This was our patient, remember, who developed metastatic disease while she was on her adjuvant endocrine therapy, and she has an ESR1 mutation and an activating PIK3CA mutation.

[01:00:34]

Posttest 4

What are you going to choose in the first-line setting for this patient?

Speaker: Polling is open. Please vote. We will allow a few more seconds for responses. We will go ahead and close that poll and share.

Dr Iyengar: All right. There is room for debate here, but we have got 38% saying fulvestrant PIK3CA inhibitor, 27% the triplet invo, palbo, fulvestrant, 24% saying fulvestrant and CDK4/6 inhibitor. Per the guidelines, the recommendation for this high-risk patient, because she recurred while she was on her adjuvant endocrine therapy and is found to have a PIK3CA mutation, INAVO120, and I know I reviewed that trial very fast, but that study showed a major PFS benefit for the triplet and an early, pretty clear indication of an OS benefit, although the data are immature when you use the triplet combination in that high-risk population here.

[01:01:59]

Take Takeaways for Advanced HR+/HER2- Breast Cancer

The key takeaways mainly are essentially we are now using a biomarker-driven approach even as early as the first line, we reviewed the inavo listed case here. But certainly, as you get into the second line, ESR1 mutations, PIK3CA mutations, and AKT, PTEN, pathway alterations guide our treatment selection in the second line and beyond.

[01:02:20]

Resources for Optimizing the Use of CDK4/6 Inhibitors in HR+/HER2- Breast Cancer

I will leave you here with some additional resources. Thank you for giving me 3 additional minutes in this case or in this webinar, and I hope you found it interesting. Enjoy the rest of your day. Thank you.

Q&A

Speaker: All right. Dr Iyengar, do you have a couple of minutes to take—there is a few questions I saw that came into the Q&A. Are you able to take those?

Dr Iyengar: Yeah. I sure do.

Speaker: Okay. Would you like to read those out, or should I read those to you?

Dr Iyengar: Let me see.

Speaker: And if anyone has any other questions, please enter those into the Q&A section in Zoom. If you want to go ahead and advance your slide also, Dr Iyengar. Yes. We have that one final. If you please text or please answer, if you plan to make any changes in your current practice based on what you learned today. If you could answer that poll, that would be great.

Dr Iyengar: All right. I will go ahead and close that one out. Thank you very much.

Speaker: Perfect. Then I believe we have 1 more slide that has a QR code on it. There we go. Okay. If you would like to take a moment to enter 1 key change that you plan to make in your clinical practice based on this education today, that would be very helpful in us developing further material for you all in the future. Okay. Then if you could go forward 1 more slide, Doctor Iyengar.

Dr Iyengar: There we go.

Speaker: One more. I keep thinking it is almost over. Okay. There you go. All right. Now let me just say the close out here. While you have a chance to answer any further questions, there are a couple of QR codes on the screen. There are also links in the chat panel for those of you who are not able to use the QR way to access the materials. One will be to the downloadable slide deck from today’s presentation, so you will have that as a reference, and then the second will be to the program evaluation link for you to complete in order to claim your continuing education credit. It is important to note that you need to log in to or create a CCO account at clinicaloptions.com, and also please claim your credit within 30 days as credit for today’s program will expire after a 30-day timeframe. Again, Dr Iyengar, I will be happy to read those questions to you.

Dr Iyengar: Yeah. That would be great.

Speaker: Okay. How do you decide on adjuvant therapy when clinical features suggest high risk but the Oncotype DX score is low?

Dr Iyengar: That is a great question. I think certainly the first question is whether or not you are going to use adjuvant chemotherapy, and I would say that the data are quite robust for using the Oncotype platform for determining the benefit of using chemotherapy. Of course, that depends on nodal status and menopausal status as well. Now, for certain really high-risk anatomic features, like if we are talking tumors that are 5 cm or greater or nodal burden that is more than 4 nodes here, that is where I think that we have less data to support the use of a genomic platform to de-escalate therapy. I would have conversations with patients who have high anatomic risks about still using chemotherapy. Then, as we get into the selection of CDK4/6 inhibitors, it was really the NATALEE trial that allowed for the use of a genomic platform to select whether you are going to use ribociclib or not. There I would really follow the trial inclusion criteria to help guide whether you are going to use a CDK4/6 inhibitor despite a low genomic risk score. If they have the other high-risk features like anatomic or histologic risk features that would make them eligible for the trial, then certainly a CDK4/6 inhibitor would also be an option.

Speaker: Excuse me. The second question, Dr Iyengar, is how long does it usually take to get genomic test results and how does that timing impact your treatment decisions?

Dr Iyengar: It is a good question. I think it depends on the platform that you use. My experience with Oncotype, for example, has been as early as 2 weeks. I have had some take up to 4 weeks. I know there are some platforms that will say anywhere from 2-6 weeks. It really depends a bit on which platform that you are using. That being said, as I mentioned with the NATALEE trial, there was flexibility in terms of when you could start ribociclib. Patients were randomized up to 12 months after starting their adjuvant endocrine therapy. You do have quite a bit of flexibility for when you start the CDK4/6 inhibitors. For the chemotherapy decision, this is why I always advocate for sending that genomic score as soon as possible. At some institutions, the surgeon will order the test so that, by the time the patient sees the medical oncologist, you have those results. But even in that setting, if you get results and you are within that 60-day window of their surgery, that would be appropriate to start chemotherapy in that timeframe as well, although certainly for our high-risk patients we want to start sooner rather than later.