麻豆传媒

At the San Antonio Breast Cancer Symposium (SABCS), updated results from the phase III EMERALD trial showed a statistically significant improvement in progression-free survival (PFS) with elacestrant (Orserdu) compared with investigator's choice of endocrine therapy in patients with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.

Meanwhile, the phase III CAPItello-291 trial demonstrated that the addition of an investigational AKT inhibitor to standard fulvestrant doubled median PFS in the second-line setting for patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer.

In this third of four exclusive roundtable videos from 麻豆传媒, moderator , of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, is joined by , of Baylor University Medical Center, Texas Oncology, and U.S. Oncology in Dallas, and , of the University of Texas MD Anderson Cancer Center in Houston, to discuss the results of these two trials.

Following is a transcript of their remarks:

Rugo: Hello, I'm Hope Rugo from the University of California San Francisco's Comprehensive Cancer Center. I'm here at [SABCS] 2022 with my colleagues, Dr. Joyce O'Shaughnessy and Dr. Jennifer Litton. And we are going to have a roundtable and discuss some of the really exciting new developments and updates on certain studies that were presented here at the meeting. And we hope that you enjoy our discussion.

It's really exciting to see the monarchE data and have something to offer our patients with high-risk ER-positive disease and a definition of high risk. And we're waiting to see the NATALEE data with 3 years of ribociclib [Kisqali]. So that'll be interesting. But we also saw a lot of very interesting data about new endocrine agents, the oral selective estrogen receptor downregulators [SERDs]. So we know we have a number of them, camizestrant with a positive phase II trial called SERENA-2. So we'll wait for the phase III data there.

Imlunestrant that can be combined with abemaciclib [Verzenio], same company, so that was interesting data. And then giredestrant that's being tested in combination with a number of agents. And then the oral SERD which has the only phase III data is elacestrant from the EMERALD trial.

And when we first saw that data, people were a little disappointed in the progression-free survival, broader in the ESR1 mutant. But we saw some really interesting data here presented by Virginia Kaklamani about the duration of exposure to CDK4/6 inhibitors. What did you think about that, Joyce?

O'Shaughnessy: I think it was helpful because at the end of the day, when you look at the EMERALD data, so it was elacestrant, it was in CDK4/6 inhibitor-pretreated patients -- so it's one of the few phase III's we have there -- and elacestrant versus endocrine therapy of physicians' choice, which was fulvestrant or an aromatase inhibitor.

And there is a big drop-off. Both PFS curves are right on top of each other. There's a big drop-off because the patients are endocrine therapy-resistant. But then the curves split and then the patients who are endocrine therapy-sensitive, they do better with elacestrant, but the medians are very, very close to each other because it was a big drop-off there. But then they split.

And particularly interestingly, as you know, in the ESR1-mutant population, which really has taught me that that means endocrine therapy sensitivity, those ESR1 mutations are still endocrine therapy-sensitive disease. But the problem is, how do we pick the patients who are endocrine therapy-sensitive?

And that's why this analysis was interesting because they looked at patients who were on their antecedent CDK4/6 inhibitor less than 6 months, 6 to 12 months, more than 12 months, or even more than 18 months -- and with every step up in duration of the CDK, you had a better outcome with elacestrant versus endocrine therapy of physician's choice.

There seemed to be a cutoff at 12 months. If you were less than 12 months, there wasn't very much difference. But if you were longer than 12 months, there was a much bigger difference. And when you look at the ESR1-mutant patients, about half of the patients were ESR1-mutant. And you're more than 12 months on CDK4/6, they were up to 8.6 months median PFS versus endocrine therapy, so a nice improvement.

But I liked what Virginia Kaklamani said from the podium. She said that if you look at the wild-type, the ESR1 wild-type population, which is in the supplement of the JCO [Journal of Clinical Oncology] paper, they didn't revisit those data, but the hazard ratio for PFS, elacestrant versus endocrine therapy physicians' choice, was about 0.82. So there's a trend, it's not a big difference there, but you see the same thing, this big drop-off, the curve split. And she made the point, and we know this, there are patients who still have endocrine therapy-sensitive disease, but they have wild-type estrogen receptor. And ... the bone only's, who are slow progressors, they've done great. Those are the people that they may be still wild-types.

But it was helpful. We just need more tools and that's an easy one. Less than a year, more than a year on which will be probably like 80% of the patients, 75%, 80% will go at least a year on CDK.

Rugo: They divided it up even more. So, it's always hard when you make little tiny groups, but like 6 to 8 months, 8 to 12 months, etc. And it does look like there's even improvement in greater than 6 months, at least in the ESR1-mutant population in particular, it just wasn't as striking as greater than 12 months. But I was impressed by the landmark analyses too, which I think can be helpful, which really showed that many more patients were on therapy at the landmark analyses based on this CDK4/6 inhibitor exposure.

So, elacestrant has been submitted to the FDA with a PDUFA [Prescription Drug User Fee Act] date in February. So we may have an oral SERD next year, so it'll be interesting to see. We all hope so.

[Editor's note: Since this video was recorded, the FDA approved elacestrant for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.]

O'Shaughnessy: Get rid of those shots.

Rugo: Yeah. Rather than the fulvestrant. We'll see.

But there also was, we talked about some of the other targeted agents that we use at San Antonio here, and the one phase III trial which really made the news was capivasertib in the CAPItello-291 trial, where patients who had metastatic disease that had progressed on an aromatase inhibitor were randomized to receive fulvestrant with placebo or capivasertib, which is an AKT inhibitor. What did you think about that data also, Joyce?

O'Shaughnessy: I thought it was very positive, very encouraging, because that's only the second phase III trial we have in the post-CDK4/6 inhibitor-pretreated patients. We know that escape through the PI3 kinase pathway is a very important mechanism of resistance to CDK4/6 inhibitor therapy. And so CAPItello-291 was essentially a second-line trial of fulvestrant-placebo versus fulvestrant plus capivasertib, which is an oral inhibitor of AKT.

And [there were] two co-primary endpoints. One, the intent-to-treat population, and then the other is the patients who had an alteration in the PI3 kinase-AKT pathway. So they could have an activating mutation, PIK3CA or AKT, or genomic loss of PTEN. And that was around 50%...

Rugo: 40%.

O'Shaughnessy: ... 40% of the patients. And it met its primary endpoint of a significant improvement in PFS in the intent-to-treat population, and [was] even more impressive in the genomically altered population. They did show the curve to the wild-type patients too, taking out the mutationally activated group. And there was still a nice improvement in PFS for those patients, because, again, you can still have activated that pathway without having one of those three mutations. There's a lot of other mutations in that pathway, and there's ligands upstream that can activate that pathway too.

So it was a very positive trial. They showed the survival curves in the intent-to-treat, as well as in the genomically altered, group. And gee, they're looking promising. They're not significant yet, but they're both looking promising.

Then in terms of toxicity, diarrhea was over 70%, about 9% grade 3. And then rash about 32%-ish, 38%-ish. And then some fatigue, some nausea, not much in the way of hyperglycemia, which makes it different than alpelisib [Piqray], but still an agent that's going to have to be worked with in terms of toxicity. But I would love to have it in the practice. For one, we don't have anything to inhibit AKT mutations, which can evolve and become acquired PTEN loss, about 5% of the patients had PTEN loss, about 5% had the AKT. And for PIK3CA mutations, we didn't see that subset specifically, because of course you're getting into small numbers, but it'll be an alternative to alpelisib, and we'll see. Let's see the publication, let's see a little bit more data. Maybe there'll be that subset on the forest plot. We can just have a look and have a little confidence specifically in that.

But I think it'll be, certainly, they allowed patients in who have hemoglobin A1c's up to 8, so that's going to open up the funnel because we can't do alpelisib unless it's under 6.5, right? So it's another alternative for patients and that's a super important pathway.

Rugo: Yeah, I agree. I mean that you could have been a diabetic on oral meds too, which is really nice. And it was only 2.3% risk of grade 3 hyperglycemia, although there were other patients who had milder arises. But, since we really struggle with being diabetologists when we're a breast oncologists and most of the drugs used today were approved long after I did my general medicine training, like Januvia [sitagliptin], I know them all from the television.

So it's nice not to have to deal with that. But there is still rash and diarrhea. But I think it was impressive as well, I agree. The intent-to-treat and then the altered pathway population, all of those tests were done on tissue. So the 16% of patients in the [capivasertib] arm had unknown mutation status -- no tissue, the tissue wasn't any good, whatever the issues were. So looking at the cell-free DNA is going to be really helpful because the question we really need to answer is, does it work in the non-altered population? And I think we need to solve the problem of that 16% to know for sure.

So, we hope. It's met its endpoint. Hopefully it will be available to us, probably not until the end of 2023, but who knows. And so that's really exciting.

Watch episode 1: New Developments in HER2-Positive Breast Cancer at SABCS 2022

Watch episode 2: Anti-CDK4/6 in Metastatic Breast Cancer Showed Further Benefits at SABCS

Comment