Dr. Virginia Kaklamani:
Hello and welcome to The ASCO Post Roundtable Series on Next-Generation Therapies for Meta-static Hormone Receptor–Positive Breast Cancer. I'm Dr. Virginia Kaklamani from UT Health in San Antonio. Joining me today, I have two of my colleagues, Dr. William Gradishar and Dr. Komal Jha-veri. Bill, would you like to introduce yourself?
Dr. William Gradishar:
Sure. Thank you. Bill Gradishar, Professor of Medicine at the Lurie Cancer Center of Northwestern. Glad to be here.
Dr. Kaklamani:
And Komal?
Dr. Komal Jhaveri:
Hi. Komal Jhaveri, breast medical oncologist at Memorial Sloan Kettering Cancer Center and very delighted to be here with both of you.
Dr. Kaklamani:
So today, we'll be discussing the treatment and management of metastatic breast cancer with three patient cases. Our next installment will focus on a patient with metastatic breast cancer with a PIK3CA mutation. So let's move on to the case. This is LB. She's a 45-year-old premenopausal woman, diagnosed with a right ER 90%, PR 80%, and HER2 1+ breast cancer. She undergoes partial mastectomy, showing a 1.5-cm tumor with one positive lymph node. She receives adjuvant chemo-therapy with an anthracycline and taxane and radiation therapy. She started on ovarian suppression and aromatase inhibitor and abemaciclib. She completes two years of abemaciclib and continues on the OFS and AI, and 2 years later, she presents with increased fatigue and weight loss. Imaging shows two liver lesions and multiple bone metastases. A liver biopsy shows that her tumor is still ER/PR-positive, now 50% and 40%. HER2 again is 1+. So the first question is would you perform any other testing at this point?
Dr. Jhaveri:
So yes, I think this is a very interesting question. This patient certainly is on endocrine therapy, has high-risk disease, completed her two years of a CDK4/6 inhibitors, but while on her aromatase in-hibitor therapy, her adjuvant endocrine therapy now is found to have these liver lesions for which she had the biopsy. I would run a next-generation sequencing from the sample to try and identify if there is presence of mutations, particularly PIK3CA mutations given now that we have data from a trial that evaluated a triplet regimen including a PIK3CA inhibitor with CDK4/6 and endocrine ther-apy. But she also just completed her CDK4/6 inhibitor therapy. So it would be nice to see what the next-generation sequencing would enlighten us with in terms of the tissue profile to then best de-cide how do we treat her cancer.
Dr. Kaklamani:
So you presented the INAVO120 data. Would this patient fit the criteria for that trial?
Dr. Jhaveri:
So that's a fantastic question. In that study, we only had four patients who had had prior CDK4/6 inhibitor in the adjuvant setting given the timeline of when the trial was designed and conducted. So I think, we're probably going to see a lot more patients now that we're treating a lot more pa-tients with adjuvant CDK4/6 inhibitors that might fall in that bucket. But we don't necessarily have that data set specifically addressing that question about what do we do when we already have somebody who's progressed on an adjuvant CDK4/6 inhibitor.
So I think we might still have to go with what we used to do with HER2-positive disease. We didn't have that data when we started developing anti-HER2 therapies in the metastatic setting and we started using those same anti-HER2 therapies in the adjuvant setting. And we kind of used that 12-month treatment-free interval as a way of trying to guide our decisions about rechallenging with the same therapy in the metastatic setting given the robustness of the data that we have in the metastatic setting. So I might have to think about that same treatment-free interval because we just don't have any other data set yet to guide us otherwise.
I think, while we don't have approval for inavolisib yet, based on the INAVO120 study that evaluat-ed this triplet, that would apply for a patient like this who's progressed on or within 12 months of their adjuvant endocrine therapy—I think that definitely has stirred a lot of interest in evaluating these triplet-based regimens in other clinical trials that are currently underway. And so I think we have such trials available for patients at our institution here, and they're available many places as well. So I would look for these PIK3CA mutations to see, potentially, if I could enroll this patient with this triplet regimen on a clinical trial.
Dr. Kaklamani:
And that's an important point, Kamal. We've learned so much in medical oncology because of clini-cal trials, and so encouraging our colleagues, as well as patients, to participate in these trials is key to try to find more effective therapies.
Dr. Jhaveri:
Yeah, especially in the first-line setting where we have such effective therapies, but not for this particular patient group, perhaps.
Dr. Kaklamani:
Now Bill, this is a patient that was on abemaciclib 2 years prior, completed her therapy. Now, she's still on the AI and developing metastatic disease. What would you give her, regardless of that next-generation sequencing because inavolisib is not available right now. What would you give her as first-line therapy?
Dr. Gradishar:
Well, she's far enough out from the CD4/6 inhibitor and with all the caveats that Komal just out-lined, I would still think about revisiting a CD4/6 inhibitor in the first line setting. She's a few years out from that. The other point would be, do you feel compelled to use another AI or could you use fulvestrant instead. You have to play three-dimensional chess a little bit because you're thinking forward, what combinations might I use if this patient continues to be an endocrine-sensitive pa-tient?
So if you use fulvestrant with the CD4/6 inhibitor, and we know that if you use an AI or fulvestrant, combined with a CD4/6 inhibitor, it's similar. You're not going to get a different outcome. But the implication may be, that if you've used fulvestrant, you may be more limited in subsequent combi-nations with targeted therapy because, for instance, some of the PI3-kinase inhibitors currently available are combined with fulvestrant. So that would raise the question, are you going to go back-to-back with a fulvestrant-based regimen if you progressed immediately before? So back to what your question was, I'd probably give her a CD4/6 inhibitor plus an AI.
Dr. Kaklamani:
Interesting. That's important to recognize because we have some data without alpelisib and AIs as well as fulvestrant, but we don't have that data with capivasertib. The data that we have is just with fulvestrant. If we were to give her fulvestrant in the first line, which I would be inclined to do be-cause she just had disease recurrence on an AI, then you might get stuck in that second-line set-ting. Now, this patient did get fulvestrant, but Komal, would you give fulvestrant to this patient or would you switch her to a different AI?
Dr. Jhaveri:
No, I would give her fulvestrant as well. I think because she progressed on the AI, I feel like, and she's already had a CDK4/6 inhibitor, thankfully, 2 years ago. So I think we don't have necessarily data for that either. We didn't have data for our first-line therapies where patients have already had CDK4/6 in the adjuvant setting. But we do have data for fulvestrant when patients progress on their aromatase inhibitor therapy. So I would definitely do that. Certainly Bill's point is very well taken. For an example, even in the CAPItello-291 study, prior SERDs were excluded. So we don't know what a fulvestrant regimen would do with capivasertib if the patient has already progressed on fulvestrant. Having said that, I think the data that we have from the lab where we looked at PI3K inhibitors along with endocrine therapy and the crosstalk, which is why we do what we do. We combine these two because of this crosstalk that we want to address.
The best combination that they looked at was with fulvestrant, which is why all these registrational phase III trials were also looking at fulvestrant as the combination partner. I do think that it's im-portant to have some endocrine therapy to address that crosstalk. While we don't have definitive data for fulvestrant beyond fulvestrant, I still do think that just having those two combination ther-apies and relying on that to address the tumor would still be something I would approach for a pa-tient who might be appropriate for another line of endocrine-based regimen given the mutation status if we have that.
Dr. Kaklamani:
So a great point as well. So she received denosumab, ovarian suppression, fulvestrant and ribo-ciclib, and has treatment response lasting 14 months, at which time, she's found to have two new liver lesions and progression in her bone disease. So what would you do next?
Dr. Jhaveri:
So again, I think this is what we would expect if anything, from a first line fulvestrant-based regi-men on a patient who's progressed on an adjuvant AI therapy, we usually see about 10, 12 months. So this is 14 months. She did that. We, again, have progression and two new liver lesions as well. I think this would be a time again to do a liquid biopsy to see what kind of mutations we might be able to uncover to then be able to guide our next line of therapy based on that and use targeted options if we find mutations that might be targetable.
Dr. Kaklamani:
So she does have a liquid biopsy. She's found to have a PIK3CA mutation. Bill, what would you offer this patient at this point?
Dr. Gradishar:
Well, it's back to the comments I made before. I think in this patient, you still have clinical evi-dence that she's endocrine sensitive by the PFS duration on the last course of treatment. You also have liver metastasis. But that said, I don't think it's prohibitive obviously to give another a course of endocrine therapy simply because the patient has liver metastasis or a couple of them. So I think that the issue is going to be how do you leverage the PI3 kinase mutation having already had ful-vestrant as well as an AI. I would try and do it, and I guess the question is we're in a data-free zone, that you could, again, revisit fulvestrant, but unless I'm mistaken, I'm not aware of any clear data showing that back-to-back fulvestrant-based regimens are necessarily data-driven at this point.
Dr. Kaklamani:
So you would obviously also give a PI3 kinase inhibitor?
Dr. Gradishar:
Yeah. I am sorry. Of course. Combining it with... And in this case, I'd give Capivasertib.
Dr. Kaklamani:
So we have two PI3 kinase inhibitors approved: alpelisib and capivasertib. Komal, How do you de-cide between those two?
Dr. Jhaveri:
We have obviously alpelisib and we have capivasertib, an AKT inhibitor. I think the two have dis-tinct toxicity profiles. So when we think about alpelisib, we do struggle a whole lot with hypergly-cemia, diarrhea, rash, some stomatitis. With capivasertib, the two most common things that we really encounter are diarrhea and rash. I think we, as oncologists, have really become experts in managing diarrhea really, really well. I'm not sure I can say the same skill set applies when we think about hyperglycemia management. I feel like my bar gets complicated after metformin and figuring out what newer agents—if a patient acquires hyperglycemia, we have to seek help from our endo-crinology colleagues, which might be sometimes tricky to get for a patient. So I think given the tox-icity profiles and be able to manage diarrhea rash with prophylaxis primarily for the rash with anti-histamines, as soon as the patients start and guiding our patients for diarrhea management very proactively, I would choose capivasertib and I would still favor doing that with fulvestrant in this particular case, just because we don't have, unfortunately, the AI data with capivasertib yet.
Dr. Kaklamani:
I do something similar as well. I practice in South Texas, so hyperglycemia tends to be a major issue for my patients that are at least, a majority prediabetic, if not diabetic. Capivasertib tends to be a little bit kinder. The results from CAPItello, the inclusion criteria of CAPItello was a higher hemo-globin A1C. So feel a little more comfortable with that in those patients, but we’ve been using al-pelisib since it was approved, and it’s definitely an effective drug, as well.
So the clinical takeaways from this case, this is a case with PIK3CA mutation. These mutations arise in around 40% of hormone receptor–positive breast cancers, and these are mutations that are seen in the primary tumor, as well as the metastatic side. So either biopsy would capture them. Combi-nation endocrine therapy with alpelisib, capivasertib, and—when it is approved—inavolisib, as well, has shown improved efficacy in patients with tumors that have PIK3CA mutations. As far as side effects, things to consider with these agents are going to be stomatitis, hyperglycemia, diar-rhea, and rash. So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in metastatic breast cancer or visit ascopost.com.
