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Precision in Practice: Navigating AE Mitigation in the Era of Targeted Treatments to Elevate Clinical Outcomes for Patients With High-Risk HR+/HER2- Breast Cancer

Fundamentals II: Advancing Therapy in HR-Positive/HER2-Negative Metastatic Breast Cancer

Kimberly Podsada:

So thank you all for joining. I am now going to be presenting advancing therapy in hormone receptor-positive/HER2-negative metastatic breast cancer.

Treatment Landscape HR+/HER2- MBC

Look how far we have come over the last 10 years. This is our treatment landscape for this particular patient population.

And it is amazing what we have accomplished over the last 10 years, from 2015. Anything before that is, you know, some good therapies, some very relevant and important therapies. But at this point, from 2015 moving on, we have so many different targeted therapies, working at the cell cycle with our CDK4/6 inhibitors. Then, we have all of our ADCs as well. So, it is just a plethora of choices now, which is really exciting because we have had this unmet need in this patient population. And now we are seeing all these different ways in which we can target these alterations, these mutations, and these ways that cancer can become resistant to endocrine therapy.

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

Looking at some of those pathways and that mechanism of endocrine resistance, here we are looking at the extracellular as well as our intracellular means of alterations. We have this pathway known as our PI3-AKT-mTOR-P10 pathway, and this is a very healthy and normal pathway in cell cycle division. But when we start having those alterations, that can then cause cancer proliferation as well as it can cause endocrine resistance.

So you can see visually on this slide here where we have our inhibitors coming in, our AKT inhibitors, our PI3 kinase inhibitors. Now we also have SERDs. So this selective estrogen receptor degradator is also really important, and I am going to be talking about those as well. But we really see this alteration in the cell cycle, and this causes activation of growth factor signaling pathways and the dysregulation of the estrogen pathway. So, we are going to be looking at the ESR1 mutations as well as this robust pathway where we now have several targeted therapies.

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

We still have this unmet need, though. And all of these therapies are really trying to address that need. So for our first-line, which is our standard of care endocrine therapy plus a CDK4/6 inhibitor in our first-line, we are seeing patients on therapy over two years now without disease progression. And this is phenomenal. This was practice-changing. So this has become our first-line therapy.

When we are moving into our second-line therapy, we are really seeing that median PFS drop maybe down to six months. Then, we are moving into our third-line therapy, and often that is with chemotherapy.

Nowadays, we do have more targeted therapies. So, I expect to see these numbers and graphs change over time but right now it is still not clear what to do after first-line therapy or which mutation to target first.

Skill Building and Feedback IIA: 1L Therapy Planning in HR+/HER2- MBC

So for our first skill building feedback question, we are going to review this patient, discuss with the faculty. This is where I really want to hear your comments, your questions. This is your opportunity to pick our brains and to share your insights as well.

A 52-year-old post-menopausal woman with hormone receptor-positive/HER2-negative metastatic breast cancer, who was originally diagnosed with a stage II PT2N1 grade 3 invasive ductal carcinoma. She was treated with lumpectomy, lymph node biopsy, adjuvant TC radiation, and her five years of aromatase inhibitor plus ovarian suppression.

She reports a new onset of back pain and a cough. Her current imaging shows three lytic bone metastases and three small lung nodules, no liver lesions. Biopsy confirms metastatic breast cancer, ER is 90%, PR is 20%, and HER2 is negative, good performance status, and her comorbidities include controlled hypertension with this mild osteopenia, which she might have developed when she was on her adjuvant therapy.

How would you explain the rationale for this first-line endocrine therapy plus a CDK4/6 inhibitor to this patient? Please send in your comments.

I will be taking a look, and I would love the faculty to also jump in and share their insights also on, now we are talking first-line metastatic and introducing a CDK4/6 inhibitor to the endocrine therapy. What is your typical discussion with your patient?

We have a comment here. Sounds like letting them know that everything is adjustable depending on their needs is most important. That might've been layover from Kayla's section. So now we are moving into our metastatic setting.

Kayla, how would you treat this person sitting in front of you?

Dr. Freeman: Yes, so I think I would pull out the conversations of course about our MONALEESA data, and then of course, just letting the patient know that adding a CDK4/6 paired with their endocrine therapy per our NCCN guidelines, it is a category one. We also know it has demonstrated survival OS benefit in this setting. I would talk to the patient about the data, but then, of course, I would get into those conversations about the symptoms and how well we are going to potentially tolerate therapy.

Kimberly Podsada: Yes, I completely agree. I mean, we have just such robust data now. This has just become standard of care. We are no longer doing endocrine therapy alone. The median PFS, the OS now is, I mean, again, practice-changing.

When you think about this patient who is sitting in front of you and you are preparing her to start this treatment, what are some of the baseline testings that you are considering? Do you think about genetic testing or the NGS-PCR testing for any actionable mutations at this time, bone density, lipid monitoring? So again, we are thinking about maybe some of the long-term side effects and what baseline studies are important, but what would you want done, and would you delay starting her treatment at all to get any of these tests done?

Kayla, Cierra, you want to jump in?

Cierra Ryan: Yes, so I would not delay treatment. I would do standard labs at her first visit for that, doing your NGS testing. The DEXA scan, I think, would probably be the lowest on my list of things to do just because with three lytic bone lesions, we are probably going to be starting her on a bone-strengthening agent anyways. And so probably, explaining to her that regardless of whether she has osteopenia, osteoporosis or not, she is going to be getting essentially the same treatment. But I think thinking more of the whole human perspective, and yes, a lot of this is I am 52. Is it going to give me hypercholesterolemia? Like things like that. And so, no, I would not delay treatment for any of that.

Yes, I would do her NGS testing the same day she came in. The lipid monitoring. In this case, it would be something to talk about signature testing starting from the beginning if you have that capability, but none of that stuff would cause me to delay start times.

Kayla?

Dr. Freeman: Yes, I was going to piggyback. I completely agree on all the things. I would not delay treatment either for any of the testings. Also, I think the timing of NGS testing can go either way, right? Do we do that upfront? Do we do it at the time of progression when that happens? So just some things to consider when you are treating your patient.

Kimberly Podsada: Yes, I completely agree. I mean, one of the things that, if she did not have genetic testing earlier on when she was first diagnosed, I would definitely want to know that. Is she going to be eligible for a PARP inhibitor?

Then there is always that question of, typically, I still think most people do the CDK4/6 inhibitor and endocrine therapy but then know that they also have a PARP inhibitor that they can use later on. Maybe some people would prefer to start with that. So I think that would be important information to know.

We do not always do our NGS testing at the initial diagnosis of metastatic because, again, the standard of care evidence is so robust with the CDK4/6 inhibitors. And then we also know that some mutations can be acquired once they have been on therapy. So we definitely want to capture that information if they are progressing at all. But there is no real wrong answer here, but you are right. The bottom line is we are not delaying treatment to get the answers of some of these tests.

And then, let us see. Questions, comments, any insights from the audience about your practices?

And then the final question here, we have touched on how would you explain to the patient why some baseline tests are helpful to obtain? Cierra, I really like what you said about the DEXA. You are right. I mean, we know she already has mild osteopenia. We know she is probably already going to go on to a bisphosphonate due to the lytic lesions as well. So none of this is urgent prior to starting her on therapy.

Great, thank you all so much for your comments.

And then, so we have a comment here. Getting treatment is so important to help cancer from progressing further. Treatment can be adjusted when results come in as needed.

Absolutely, absolutely. And how does the metastatic diagnosis affect the patient? So, of course, we need to think about not just the treatment and these tests and the numbers, but to really think about the patient and other support services that we can offer them emotionally, psychologically, to start adjusting their life to living now with a metastatic diagnosis.

Thank you for that.

Standard of Care 1L Treatment for HR+/HER2- MBC Is CDK4/6 Inhibitor and ET

Okay, moving forward. So we know the standard of care first-line treatment for this patient population is CDK4/6 inhibitor plus endocrine therapy. We have three that are now approved for the metastatic setting: palbociclib, ribociclib, and abemaciclib. 10 years ago was the first FDA-approved CDK4/6 inhibitor with palbociclib.

And this mechanism of action, it inhibits the CDK4/6 at that G1 to S phase within the cell cycle, causing the cellular arrest. So this decreases phosphorylation of the RB protein, which deactivates tumor-suppressive protein and preventing that cancer cell proliferation. This is a very common checkpoint, which makes it a really good key target for treating metastatic hormone-positive/HER2-negative metastatic breast cancer. And it has been approved, usually in the first-line setting with the endocrine therapy, and then in the second-line setting, often using fulvestrant.

CDK4/6 Inhibitors in ER+/HER2- MBC: Key Trial Data

Here is some of the key trial data looking at all of the studies with palbociclib, ribociclib, and abemaciclib. And so, of course, I want to look at NCCN guidelines when I am making these choices and discussing options with my patients, because we do have several options.

And they have all been indicated for first-line treatment, whether you are post, pre, perimenopause, you will be going on to ovarian suppression if you are still a menstruating woman. We did see statistical significance in median progression-free survival in all of these studies. And then when it comes to overall survival, we did see some of that data within ribociclib and abemaciclib.

So again, another key point to try and discuss with our patient, as well as side effects tolerability, which Cierra is going to do a very thorough and beautiful job after me.

Skill Building and Feedback II: 1L Therapy Planning in HR+/HER2- MBC (cont’d)

So now we have our patient scenario, next skill building. And so it is our same 52-year-old postmenopausal woman.

She has our hormone receptor-positive/HER2-negative metastatic breast cancer. Her NG testing showed no actionable alterations. Germline testing, no pathogenic variants. DEXA shows moderate osteopenia. Lipid management is already in place. She is on a statin. And so she starts her AI plus ribociclib and zoledronic acid.

Now consider a related scenario. What if this patient had instead developed metastatic disease after only eight months of adjuvant endocrine therapy and was found to have a PIK3CA mutation? So how would your treatment approach change if this patient developed metastatic disease after only eight months of adjuvant endocrine therapy and was found to have a PIK3CA mutation?

Faculty, please jump in. This is an interesting scenario and highly concerning.

Dr. Freeman: Yes, so I think for this patient, given the eight months, I mean, I still probably think she is endocrine-sensitive, so would switch my endocrine therapy backbone perhaps, right, maybe considering fulvestrant. With this PIK3CA mutation, I would be highly thinking about capivasertib for this patient.

Kimberly Podsada: Right, so now we are looking at introducing a PIK3CA inhibitor because of this mutation. And this is now challenging. As someone mentioned before about the patients now adjusting to metastatic cancer, how are we going to explain this to our patient?

She is been on therapy now for eight months, all of a sudden, is having a disease progression. We just had a conversation with her less than a year ago saying, this is standard of care, and we are getting median progression-free survival over two years of being on therapy. And now all of a sudden we are going, oh, well, your disease is progressing.

How do we explain what the PIK3CA mutation is? And how do we explain how this changes her prognosis or her treatment plan now?

Cierra?

Cierra Ryan: Yes, so the way that I read this scenario is we had this early-stage patient who was on endocrine therapy for eight months and then developed metastatic disease. We do her NGS testing. We find that she has this PIK3 mutation. And so, one, we are explaining to this woman that her endocrine therapy, she recurred through it. And so she was not the rule; she was the exception essentially, right?

Nobody wants to be exceptional in the oncology clinic. And then explaining, you are 52, we have got this great new option. You know, it is an unfortunate situation, but now is a better time than ever to have metastatic disease when we think about the options that we have.

And because we found this mutation early, she does not seem to have, you know, it says that her lipid management is under control. And so she does not hopefully have diabetes or anything. And so just telling her, well, we are going to switch one for the other. We are going to adjust things as we can. We are going to monitor for this a little bit closer than we would have been with this. And just, again, trying to explain to her, this is not curative, but this is a chronic medical condition.

We are going to treat you as anything else where you have something that you live with. You know, you have cancer, it does not have you. And so, hopefully trying to get her to understand that we have this great drug, we just got to make sure that you are going to be able to, one, tolerate it, and two, that, you know, unfortunately you relapsed pretty early, you recurred pretty early. And so, just making sure that we are getting good control early, as well as she is tolerating it as a human.

Kimberly Podsada: Right, and what are some of your thoughts? I mean, I know you are going to talk about some of this in your section, but, you know, what would be a couple of the key adverse events, side effect profile that you might discuss with her when initiating a PI3 kinase-directed treatment?

Cierra Ryan: Yes, I specifically think about hyperglycemia. And so with her being 52 and, you know, we can make assumptions based on a scenario without actually having the human in front of us when it talks about lipid management is already in place. So either she has bad genetics, or maybe her lifestyle led to hypercholesterolemia.

And so, I try not to put patients on diets when they are on treatment because things can taste different, and it is hard when I tell you that you are going to be on some sort of drug forever and now you also have to watch everything that goes in your mouth, you know. I always make the joke, if it tastes good, spit it out because it is probably not good for you. But the reality is, is that when you are on a PIK3, you really do have to be careful about those things.

And so the 52-year-old who maybe or maybe was not watching everything that she was eating and drinking, we have to hone that in a little bit. And so that is really my take-home for the Capi type of patients is like, listen, I do not want you to not have fun, but we maybe have to wrangle it in a little bit more. We are going to see her, we are going to be doing her blood anyways.

And so the one that I tend to really see a lot in clinic is the hyperglycemia. So that one's the one that I always try to drive home with people in terms of moderation, moderation, moderation.

Kimberly Podsada: Yes, and I just want to comment here about what Adrian sent in. This is just a great comment. Adrian says, I would state something like your cancer came back very quickly after the hormone medicine you took after surgery. That tells us the cancer is a bit more stubborn than usual. We also found a specific change called a PIK3CA mutation inside the cancer cells that helps it grow. Because of this, we are going to use a different plan. We will give you a targeted pill that blocks the mutation along with different hormone medicine. And the study shows this new combination can keep the cancer under control for longer. And in some cases, help people live longer than usual treatment.

Beautiful. Thank you for sharing that in, that sending that in. That is absolutely perfect.

And then Sunita also is saying, at the beginning of a metastatic cancer diagnosis, I like to explain that we have many different options in our toolbox. We typically start with our standard first-line therapy and then move into second-line and beyond as needed. I also let her know that if the cancer progresses, we will switch to a different therapy.

Right, and so, talking here about setting up realistic expectations early. And at some point there is going to be a change in treatment may be necessary, and reassure her that each step is chosen strategically based on how her cancer is behaving.

Wonderful. Thank you both for those comments. That is a really key information again, because we need to think about the person who is sitting in front of us and also being able to share this data in a way that is clinically meaningful, but connects with the patient and builds a relationship with the patient and that we hear them.

Okay, so let me move on to the next part here.

INAVO120: First-line Therapy for Early Relapse and PIK3CA-Mutated HR+/HER2- Advanced/Metastatic BC

So INAVO120 was a first-line therapy for early relapse and PIK3CA-mutated hormone receptor-positive/HER2-negative advanced metastatic breast cancer. So this was a large international randomized double-blind placebo-controlled Phase III trial where pre and post menopause women and men with the PIK3CA mutation, hormone receptor-positive/HER2-negative advanced breast cancer progressed during or within 12 months of completing adjuvant endocrine therapy. So, going back to thinking about that potential for hyperglycemia, which is an on-target effect, a fasting glucose of less than 126 and a hemoglobin A1C of less than six.

So a little less generous than some of the other clinical trials. So we really want to make sure that their hemoglobin A1C is under control is less than six and, of course, measurable disease. So inavolisib is a 9 mg oral therapy given once a day, and it was paired with palbociclib standard dosing and fulvestrant compared to placebo palbociclib and fulvestrant. And our primary endpoint, of course, is usually median progression-free survival, and our key secondary endpoints as well.

INAVO120: Key Endpoints

So our key endpoints here show that the median PFS was 17.2 months with the addition of inavolisib versus placebo, which was 7.3 median progression-free survival. So significant improvement.

We also saw that more patients were having a complete or partial response, 72% of patients versus 28% of patients on the placebo arm. And as we discussed, some of the side effect profile includes the neutropenia, thrombocytopenia, stomatitis, hyperglycemia, nausea, diarrhea, and rash. So I often think of trying to get many of these things already under control if they already seem like they are borderline, especially that hyperglycemia, it is an on-target effect, and it is important to be aware of that and to inform your patients of it too.

Interestingly though, I think that it is a good sign when only 6.8% of the patients have to stop the inavolisib due to toxicity and 70% did have dose interruptions or dose reductions. So again, we are tailoring the dose for the individual, trying to find the best dose that is most tolerable for them to keep them on therapy.

Skill Building and Feedback IIB: Progression on 1L CDK4/6i + AI

Our next skill building.

So we have our 52-year-old postmenopausal woman with hormone receptor-positive/HER2-negative metastatic breast cancer, and she has been on her aromatase inhibitor plus ribociclib for 24 months. She now reports new worsening abdominal pain, and the staging scans showed that she has disease progression with new liver lesions. Liver biopsy confirms metastatic breast, ER 70%, PR 20%, and now HER2 ultralow. So IHC zero, but less than 10% staining positive, so ultralow. Tissue NGS identifies a PIK3CA mutation, that is a very common mutation, and liquid NGS identifies an ESR1 mutation as well as confirms the PIK3CA mutation.

This scenario is focusing on the repeat biopsy, repeat molecular testing, and now how to explain biomarker-driven next-line treatment planning after progression on her first-line CDK4/6 inhibitor and endocrine therapy.

So is a repeat biopsy needed for this patient, and would you also obtain repeat NGS testing? So we just answered that question by reading the scenario. We did repeat the biopsy. We did a tumor specimen as well as liquid NGS, and they did show that she had mutations.

So I would really like to ask the faculty and all of you to send in your comments and discuss how you would now explain the significance of these two mutations. And again, in the plain language. Now, I think Adrian had sent in a comment, and that was very helpful. So we do know that we need to use some simplified language to describe to our patient what these mutations mean.

And then how would these results change your next slide treatment approach, and what efficacy and AE consideration would you discuss with this patient? So I am just going to give us a few minutes for the faculty discuss, because I do need to move on.

What are your thoughts when you see this, and now how are we going to explain these mutations to our patient, and what do we do next?

Dr. Freeman: Yes, I mean, I will start with it. I think that we can highlight, I know we have talked about the PIK3CA mutation as far as the ESR1 mutation, right? I think we highlight that for one, our patient has gotten great benefit out of their CDK4/6 inhibitor and their AI for 24 months. So that is a good thing. But on the other hand, we know that over time, they can acquire a resistance where their endocrine therapy just does not work as great anymore. Data shows us, and again, this is from our EMERALD study, but it shows us that when you have been on endocrine therapy for at least 12 months, the benefit of the median progression-free survival is even better. So we would benefit from switching you to a drug like elacestrant when it comes to that ESR1 mutation. And I know, of course, we have talked about the PIK3CA.

So I will not, for the sake of time, I will not go into much about that, but that is how I would explain it. More of it being like this acquired mutation that you have developed.

Kimberly Podsada: Right, great, thank you. And I do want to just comment here about Adrian. I really appreciate your honesty here. Often my challenge is translating complex medical concepts into basic language, and oncology is complex.

Absolutely. I will use visuals. I will draw pictures. However the patient best learns, I will try to present a variety of different teaching and learning tools. And again, just trying to reinforce and partner and making shared decisions. And so that they feel informed in that process as well.

Targeted Therapies for Alterations in HR+/HER2- MBC by Clinical Trial and Approval

Here are our targeted therapies for alterations and some clinical trials and approval. So yes, when we are looking at our ESR1 mutations, we have our elacestrant and now imlunestrant as well. Camizestrant is probably soon to be approved, but it is still investigational.

Then we are moving into our PIK3CA-AKT1-P10 mutations. We have alpelisib, capivasertib, and inavolisib. So all of these have been approved.

We have our ADCs. And then we also have a new investigational agent, which I will just touch on briefly in a couple of slides. But this is also now for ESR1 mutation. It is a PROTAC, estrogen receptor degrader, vepdegestrant, there we go. And that is currently investigational.

Disease Progression After Treatment With AI + CDK4/6 Inhibitors

And so, disease progression after treatment with our CDK4/6 inhibitor and AI, we do see in these ESR1 mutations that up to 20-30% of patients who have metastatic breast cancer and received AI therapy do develop this mutation.

When someone has been on an AI and a CDK4/6 inhibitor, that percentage can increase up to 40%. What is interesting, though, is that this mutation prevalence in the estrogen therapy, a naive patient is less than 1%. As Kayla mentioned, this is really an acquired mutation.

This is just a simple visual to show you how the normal cell, how the estrogen will bind, and then how those mutations occur right at the estrogen receptor. So we are looking more at an extracellular mutation.

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

Again, looking at our NCCN guidelines, what do I do next? What has a category one or a category two rating? What combinations are available for my patient? So we talked about the fulvestrant, inavolisib and palbociclib for that endocrine-resistant, early-progressing patient.

Alpelisib and fulvestrant, if they have a PIK3CA mutation, capivasertib and fulvestrant. So it is interesting, capivasertib is actually an AKT inhibitor, but it is indicated if you have a PIK3CA mutation or a P10 mutation as well. So a little bit more broad indication. Then, as far as our ESR1 mutations, we have our elacestrant and imlunestrant as our SERDs.

FDA-Approved Therapies for ESR1-Mutated MBC

Elacestrant for our ESR1-mutated metastatic breast cancer, elacestrant is 345 mg once a day with food. It is indicated for our estrogen-positive/HER2-negative metastatic breast cancers with the ESR1 mutation following progression of at least one line of endocrine therapy.

It was the first SERD approved. And as Kayla mentioned, that median PFS for the whole population, 3.8 months versus 1.9. But if your patient has been on endocrine therapy and a CDK4/6 inhibitor for more than 12 months, that median PFS does increase to 8.6 months versus the 1.9 months.

And for imlunestrant, we have a 400 mg pill that is taken once a day. Again, same patient population, hormone-positive/HER2-negative, ESR1-mutated, and at least one previous line of endocrine therapy in the metastatic setting. And of note, what is important is to see what is coming down the road. So when this was paired with abemaciclib, it did show maybe to be the most effective choice for ESR1 mutations with no prior CDK4/6 inhibitor, though. So that is still pending approval. And the median PFS was 5.5 months versus 3.8 months of endocrine therapy alone.

Novel Agents for ESR1-Mutated MBC: Next-Generation SERDs

So for some of the novel agents, as I mentioned, imlunestrant plus abemaciclib to be determined, but we did see that the PFS was 9.4 months versus 5.5 months.

Camizestrant plus a CDK4/6 inhibitor versus AI and CDK4/6 inhibitor. So this is just interim analysis, but we did see a 16.0 median progression-free survival versus 9.2. Interesting study. I probably will not have time to go into it with much detail, but I will just say that in this study, they did use ctDNA. And when someone developed an ESR1 mutation, they were able to cross over to the camizestrant arm. So really curious to see what that final data looks like. And giredestrant also is something that we may be seeing coming to market, and that is paired with everolimus, so an oldie but a goodie. And there is definitely room to reintroduce that again, so we may be seeing that in the future.

Novel Agents for ESR1-Mutated MBC: PROTAC ER Degrader

So here is that novel agent that I talked about. It is a PROTAC estrogen receptor degrader.

We did see some significant improvement in PFS for that ESR1 mutation, about five months versus two months. Again, just planting that seed of there are more agents coming.

PI3K/AKT/PTEN Mutations in HR+/HER2- Breast Cancer

Now, looking at the PI3-kinase-AKT-P10 pathway, we can see that the PIK3CA mutations are found in about 40% of patients with the hormone receptor-positive/HER2-negative breast cancer.

The AKT mutations represent only about 4-8% of breast cancer patients, and these mutations are associated with a poor prognosis and resistance to endocrine therapy. The P10 is a suppressor, is a tumor suppressor that regulates AKT, so the loss of the P10 function continuously stimulates the AKT, and the P10 loss is associated with a very poor prognosis, highly treatment-resistant, and this can be expressed in about 4-13% of hormone-positive/HER2-negative metastatic breast cancer patients. So, again, really important to know these mutations and know that we have targeted therapies.

FDA-Approved PI3K/AKT/mTOR Inhibitors

Briefly, no, probably not going to review all of this because I do not have much time. You will get copies of all the slides, but I do want to point out one thing about capivasertib, which is interesting when we are educating our patients about taking this medication. It is 400 mg twice a day for four days on, three days off. So this is where we have to be creative with helping our patients take a very different scheduled therapy.

CAPItello291: Capivasertib + Fulvestrant in AI-Resistant, HR+/HER2- Advanced/MBC

Capivasertib plus fulvestrant in our AI-resistant large CAPItello291 study, and I will let you review these slides in the future, but again, capivasertib is taking 400 mg four days on, three days off.

CAPItello291: Key Endpoints

So, different challenge for our patients, but key endpoints, the median PFS was 7.2 months versus 3.6 months. 26% of patients had a partial or complete response versus 8% on placebo and fulvestrant. Again, that hyperglycemia on-target effects. So something we do need to monitor. Most of the AEs though, were grade one and two and more manageable.

Posttest 2

Looking here for our posttest question number two, a patient with hormone receptor-positive/HER2-negative metastatic breast cancer, and an AK1 mutation starts capivasertib plus fulvestrant. The patient has obesity and prediabetes at baseline. Two weeks later, fasting glucose is rising, but the patient is otherwise tolerating treatment. What is the most appropriate next step?

1. Continue treatment unchanged and repeat glucose testing at the next routine restaging visit;
2. Increase glucose monitoring, start glucose lowering support as needed and coordinate follow-up;
3. Stop capivasertib permanently and switch therapy because hyperglycemia is expected to get worse or reduce the fulvestrant dose and continue capivasertib at the current dose.

Please take a moment to answer the question.

Wonderful, we have 74% of participants saying that increase glucose monitoring, start glucose lowering support as needed and coordinate follow-up.

Absolutely, this is an on-target effect. And so, either making sure baseline hemoglobin A1C is low and fasting glucose is within normal range and just having those realistic conversations with our patients about how to manage the symptoms and keeping them on therapy.

And so at this point, Cierra now is going to be taking this over to round up the conference here and talk about how to manage AEs.

Oh, rationale, sorry, there we go. Yes, the best answer is B because we know this is patient has risk factors, and hyperglycemia is a known on-target effect.