Dr. Kevin Kalinsky:
Hi. Welcome to The ASCO Post Roundtable Series on Targeting Endocrine Resistance in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer. I'm Dr. Kevin Kalinsky. I'm Professor of Medicine at Winship Cancer Institute in Atlanta, Georgia, and a breast medical oncologist. Joining me today are two of my colleagues. Dr. O'Regan, would you like to introduce yourself?
Dr. Ruth O'Regan:
Yeah. Thanks, Kevin. I'm Ruth O'Regan. I'm Professor of Medicine and a breast oncologist at the University of Rochester in New York.
Dr. Kalinsky:
Great. And Dr. Bhave?
Dr. Manali Bhave:
Thanks, Kevin. Hi there. I'm Manali Bhave. I'm a breast oncologist at Emory University in Atlanta and Medical Director of the Phase I Unit.
Dr. Kalinsky:
Great. It's great to have both of you. Today we'll be discussing the role of endocrine resistance in hormone receptor–positive HER2-negative breast cancer with three patient case studies.
Our second installment will focus on the treatment of hormone receptor–positive, HER2-negative metastatic breast cancer with a PIK3CA mutation. So case 2 is Beth, who is a 62-year-old postmenopausal healthy female who is diagnosed with a right breast invasive ductal carcinoma.
When she presents, it's with de novo metastatic disease to lung, liver, and bone. She has a liver biopsy. It is ER and PR strongly positive at 90%, HER2 1+ FISH negative. So her tumor is "HER2-low".
Her performance status is excellent. She's asymptomatic. And she undergoes hereditary genetic testing which reveals no pathogenic variants.
She receives ribociclib plus an aromatase inhibitor. And then after 12 months of therapy, the patient has progressive disease in her liver, and her liver function remains normal.
She has additional biomarker testing, which reveals a pathogenic PIK3CA hotspot mutation H1047R. So what therapy would you think about next? Alpelisib plus fulvestrant, chemotherapy, capivasertib plus fulvestrant? Elacestrant? Switching CDK 4/6 inhibitor plus AI? Trastuzumab deruxtecan or sacituzumab govitecan? So Dr. O'Regan, I'm going to start with you.
So again, this is a patient whose tumor had progressed on an aromatase inhibitor, CDK 4/6 inhibitor after just a year. PIK3CA mutation H1047R. What would you think about next?
Dr. O'Regan:
Yeah. So I think the first thing is to mention, which you alluded to, is she had... I wouldn't say rapid, but 12 months of therapy in the first line setting is a little bit less than what we typically expect to see in the first line setting.
And it's very much in keeping with the INAVO study that was just presented at San Antonio. In that particular study, they also showed in the control arm, and they all have PIK3CA mutations, a short progression-free survival.
So I think looking at these different options, the two that stand out to me are alpelisib plus fulvestrant or capivasertib plus fulvestrant. I would probably lean towards alpelisib just because I think the results of the SOLAR study are quite striking.
And this also appears to be quite a healthy patient. There's no mention of any comorbid illnesses, such as diabetes, that might be an issue for her tolerating the drug.
Capivasertib obviously is more recently approved. She would be a candidate for that since she has alterations in the AKT pathway because the PIK3CA mutation.
The other thing to mention here is there is an ongoing trial with LOXO-783, which is a novel PI3 kinase inhibitor that targets that specific mutation that she has.
And the data so far suggests that that might be somewhat better tolerated than alpelisib. But as I said, is just an early phase investigation right now.
You could consider chemotherapy like capecitabine in a patient like this, since she did progress within a year of a CDK 4/6 inhibitor. Elacestrant not an option for her since she doesn't have an ESR1 mutation.
I suppose you could consider switching the CDK 4/6 inhibitor. I think in a patient like this that possibly, or at least, is developing endocrine refractory disease, I probably wouldn't do that.
And then the antibody-drug conjugates, I don't think most of us would use those at this time point. So I would favor alpelisib plus fulvestrant, but I think capivasertib plus fulvestrant is also an option for this patient.
Dr. Kalinsky:
Dr. Bhave?
Dr. Bhave:
Yeah, I agree with a lot of the points that Ruth had made. It's actually great to have the genomic information available for this patient with the PIK3, just so that we have more options upfront on where we can go after CDK 4/6 inhibitors.
We know that PIK3 mutations can be seen in about 40% of patients. And as Ruth had mentioned, in general, predicts some resistance to endocrine therapy. And so again, not surprised by the clinical course.
In terms of alpelisib and fulvestrant vs capivasertib and fulvestrant, there are differences in the toxicities, and differences in the schedules, as well. And so you have to take both into account when making that decision between the two of them.
They're both good options. They both have a PFS benefit compared to endocrine therapy and alone. And I can't say that I lean towards one vs the other.
In general, I would say alpelisib has been more challenging for patients to tolerate, as we had talked about in an earlier segment. You can see hyperglycemia, rash, diarrhea.
Capivasertib appears to be more tolerable, with the most common side effect being diarrhea. And we're all very good at managing diarrhea now since a lot of our drugs can cause this, and so better about providing more prophylactic agents and escalating treatment for diarrhea as well.
So I think both are reasonable options. I probably would prefer capivasertib and fulvestrant over alpelisib, just because of my experience with the toxicity profiles. But also assuming that the patient is able to follow the schedule for capivasertib, which is 4 days on and 3 days off. And then I echo what Ruth was saying about the clinical trial.
So we actually do have the clinical trial open at Emory with LOXO-783. And that would be a great option for this patient as well, given that she has the exact targetable mutation.
Dr. Kalinsky:
Yeah. I have a few thoughts. One, the comparison in terms of the schedule. I appreciate you bringing this up, just with capivasertib being 4 days on, 3 days off the IV dosing.
With alpelisib, when we utilize the agent, I think it's important to talk with patients about taking a daily H2 blocker, something like... Sorry. A daily medicine like loratadine, just to make sure... Because that can help decrease the likelihood of developing rash.
The drugs, as Dr. O'Regan and Dr. Bhave, you both brought up is the drugs have never been directly compared to each other. We also don't have any sequencing data. Capivasertib was just approved.
The other distinguishing feature is that capivasertib is approved across additional alterations in the pathway. So AKT mutations, which we can see in less than 5% of ER-positive HER2-negative breast cancers, some PTEN alterations as well.
So it does increase the potential patients with an alteration that could be treated with a PI3K or AKT inhibitor. And so I do also think that this comment about these specific agents are important.
Also, just to go back to your comment, Dr. O'Regan, that you were making about the inavolisib study. So that was a study in patients with endocrine-resistant disease where it was combined with a CDK 4/6 inhibitor.
And our experience with other PI3K/AKT pathway agents made it quite difficult to combine with other drugs, just given the toxicity profile. And so when we think about the potential of combining this with other targeted therapies like CDK 4/6 inhibitors, having more targeted, more specific agents with less toxicity, I think will help us to do that.
Dr. O'Regan:
And just to your point, I just want to add just the AKT1 mutations are acquired as well. So again, just regularly checking ctDNA to see if these mutations have developed, I think, is very important.
The other one to keep in mind is HER2 because we do have data with neratinib and trastuzumab in patients with HER2 mutations. And they appear to occur more commonly in ER positive, particularly lobular cancers. So that's always something to think about as well.
Dr. Kalinsky:
Going to that point, so if this patient, let's say her tumor had progressed on an AI and CDK 4/6 inhibitor, you checked ctDNA, there was no targetable mutations that were identified. At that point, what would you do?
Would you reflex to doing tumor testing? Just talk us through how you would approach that. And would you favor metastatic tumor testing compared to primary? Just talk us through, would you repeat a biopsy? What is your general approach?
Dr. O'Regan:
Well, I think what most of us are doing now are considering doing genomics on the initial metastatic biopsy, and then doing ctDNA afterwards because it's not invasive. So I'm fairly comfortable doing that, I have to say. But I do think there are certain patients where if they have something that's relatively easy to biopsy, you might want to consider doing that.
But I think what you're talking about is primary vs acquired mutations. So PIK3CA, they are present in the primary cancer. So you can actually check for them at any point. P53 as well, although it's not therapeutically very targetable right now.
But I think as we're treating our patients, I think looking for the acquired ones really is so important. So as we mentioned, ESR1, AKT1, HER2, I think they're important to look at. If this patient who has what I would consider likely endocrine refractory disease or she's about to develop it, I would probably lean towards everolimus in a patient like this, if we didn't find a mutation.
Dr. Kalinsky:
So I want to make one comment and then, Dr. Bhave, ask you to comment on something. But in terms of everolimus, there have been data that have looked at whether different mutations are predictive of benefit. And it seems like it's regardless of whether or not patients have a PIK3CA mutation, we're seeing benefit with everolimus. So Dr. Bhave, just to also ask you the question about longitudinal collection.
So let's say progression on an AI CDK4/6 inhibitor, you do testing, it doesn't show anything. You then look in tumor tissue, nothing there. Do you keep checking circulating tumor DNA? What is your general practice? And are you finding that it's covered with doing additional blood collections?
Dr. Bhave:
Yeah. So I follow a pattern very similar to what Ruth had mentioned, where typically at time of metastatic diagnosis, we get a biopsy and we end up sending tissue genomics on that so we know upfront about things like PIK3 mutations.
And then I do serial ctDNA collections, typically at time of progression on every line of treatment. I have not had any issues with coverage. And I do think that a lot of the companies who run ctDNA analyses have very good financial programs as well.
So if there are concerns about insurance coverage, then you could email your local representative and see what kind of options they have to cover that test.
And because of the information actually potentially translating to a targetable treatment option for those patients, I really think it's important to get that serial testing done.
Dr. Kalinsky:
And when you're checking the testing, it's with tissue agnostic tests.
Dr. Bhave:
Correct.
Dr. Kalinsky:
Right? Okay.
Dr. Bhave:
Yeah. And then as Ruth had mentioned, in certain situations where perhaps the course of disease is not following what is expected with that treatment or if there's an area that's responding and one that's not, then I might repeat a tissue biopsy at that time, to not only check receptor status, but also to, again, run genomics on that.
Dr. Kalinsky:
Yeah, totally agree. Well, this was a great discussion as I think when we think about our key clinical takeaways, as I think we've highlighted, there have been advances with precision medicine and hormone receptor positive HER2-negative disease.
As we mentioned, we had had the approval for fulvestrant plus alpelisib for patients with PIK3CA mutations. As of late 2023, we had the approval of fulvestrant plus capivasertib approved for patients with various PI3K pathway–altered tumors, including AKT mutations, PIK3C mutations, and PTEN alterations.
There are additional agents targeting the PI3K pathway that are in development, including PI3K mutation-specific inhibitors such as those specifically targeting those with H1047R mutations. And there remains a need for agents with novel mechanisms of action and targets to overcome endocrine resistance.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com. Thanks so much.
