In this expert roundtable series, Seth Wander, MD, PhD, Massachusetts General Hospital, Boston, Massachusetts, leads a 3-part panel discussion on the management of patients with PIK3CA-mutant metastatic breast cancer with Megan Kruse, MD, Cleveland Clinic, Cleveland, Ohio; Janice Lu, MD, PhD, Northwestern University, Chicago, Illinois; and Kelly McCann, MD, PhD, University of California-Los Angeles.

In the second part of this discussion, our experts discuss the different agents available for targeting PI3K signaling within HR-positive metastatic breast cancer.

Click here to view Part 3 of this discussion.

Transcript:

Seth Wander, MD, PhD: Welcome back to Oncology Learning Network. My name is Seth Wander from Harvard Medical School in Massachusetts General Hospital. I'm joined today by Dr Kelly McCann from UCLA, by Dr Janice Lu from Northwestern, and by Dr Megan Kruse from Cleveland Clinic. It's my pleasure to be with you today to talk about PI3 kinase inhibitors in metastatic hormone receptor-positive breast cancer.

Kelly, prior to the development of some of the modern therapies that we're going to be talking about, we've had the mTOR inhibitor everolimus for many years. Can you tell us about current use of everolimus and then some of the toxicities that you run into in the clinic?

Kelly McCann, MD, PhD: Absolutely. Everolimus is an mTOR inhibitor, so at the bottom of the PI3 kinase/AKT/mTOR, phosphorylation cascade, and our first drug that was approved in that context. I don't think people knew that we had 40% of hormone receptor-positive, HER2-negative breast tumors with a PI3 kinase mutation, they just knew that the drug worked. Because so much of the hormone receptor-positive breast cancer is going to have an alteration or even an upregulation in the pathway as a resistance to endocrine therapy, it's very important to consider that pathway for all patients independently of whether or not they have a mutation. Current use, I use everolimus, if somebody doesn't have a PI3 kinase mutation or an AKT mutation, I can't get alpelisib or capivasertib, I'll pair everolimus with an endocrine therapy in order to capture those patients who don't have a mutation, but probably have upregulation of the pathway.

Dr Wander: Just to clarify, so these would be patients who, for example, are PIC3CA/AKT/P10 wild-type, and you would deploy it in the second line setting if you didn't have a clinical trial or if you weren't using a novel SERD [selective estrogen receptor degrader].

Dr McCann: Exactly. So my usual first line is CDK4/6 inhibitor plus AI, and second line is fulvestrant plus something to target that pathway. And which agent you pair with fulvestrant depends on whether or not they have a mutation.

Dr Wander: And Janice or Megan, any other thoughts on if you agree or disagree on where you would deploy this drug or do you use it in your clinic? Because I think there's variation.

Dr Lu: I do. I totally agree. Now, after first-line treatment with CDK and endocrine therapy, second line, if they don't have any mutation, this is the right treatment. And I also use the postMONARCH trial, CDK/post -CDK, this is the other alternative treatment if they don't have any mutations.

Dr Kruse: I think everolimus has developed a second life as we've had the CDK4/6 inhibitors and patients are in need of something else in the second line in addition to fulvestrant to give them meaningful responses in cancer control. That being said, it's available, I think it's still a tough drug. It definitely comes with stomatitis. It definitely comes with fatigue. The starting doses are a little bit imperfect, I usually have to work with dose reduction or even dose escalation in this situation. And I think the thing that really changes tolerance of it is the steroid mouth rinse to use preventatively. That really cuts down on the rate of stomatitis. And for me, that has really brought it back as a viable option where maybe it wasn't for a long time.

Dr Wander: I think that's a great point. We're going to see some common toxicities as we go through this pathway, depending on whether you're targeted at the top and the middle or toward the bottom, we may see some of the same things.

Janice, the PI3 kinase inhibitor, alpelsib, became the first targeted therapy approved in breast cancer based upon molecular genomic profiling. Seems like a long time ago, but it actually wasn't that long ago that we started to use these drugs in the clinic. Can you tell us a little bit about how you use results from the SOLAR-1 and the BYLieve studies and how that's impacting your clinical use today? I know we're going to talk about other agents later.

Dr Lu: Yeah. Now it becomes standard second line therapy with mutation and I'm so happy this is the first one that came with the mutation that got FDA approval. I do use based on SOLAR-1 and the BYLieve trial, using alpelisib for quite a period of time, since it's approval back in the early 2010s, 2012. In combination with fulvestrant versus all single agent, that's the comparison at that time. The results showed that alpelisib in combination with fulvestrant showed significant benefit. I believe the hazard ratio was like 0.65-ish. It was revolutionary and then gave us a choice at that time. Until now, with targeted therapy, with precision medicine, with PIK3CA mutation pathway.

It's a tough drug, I have to admit that. There are a lot of hyperglycemia issues for patients. And at that time, the inclusion criteria, I believe it was hemoglobin A1C was 8, so there was like 37% chance of patient with hyperglycemia on study. And then off study we also experienced quite a lot of those side effects as well, and then we need to constantly manage these patients together with endocrinologists and primary care physicians.

Dr Wander: And I think maybe we can talk about both alpelisib and capivaserib together, in terms of our clinical practice. But, Megan, capivasertib was the first AKT inhibitor approved in breast cancer therapy more recently. Can you tell us about the CAPItello-291 study in conjunction with what we just heard?

Dr Kruse: Sure. When you think about where capivasertib fits in, and where AKT inhibitors fit in, this is upstream in the pathway, right? And so that has, potentially, implications for activity as well as tolerability and anticipated side effects. And so, in CAPItello-291, what we have to keep in mind is, this population, again, second-line therapy in combination with fulvestrant. However, it's a little bit more of a real-world population for our current treatment patterns, because more of these patients receive CDK4 -6 inhibition than we saw in SOLAR-1 —that was rectified a little bit in BYLieve, we had more patients treated with CDK4 -6 inhibitors— but this represents the kind of patients we're seeing. A little bit more inclusive from an A1C standpoint, because we think that being higher up on the pathway, there may be less hyperglycemia, and that's actually how it played out in real life. For me, that was great, because more of my patients don't have A1Cs right around 6.5, they may be higher than that.

But what we did see was a very reassuring increase in progression-free survival with the combination of capivasertib and fulvestrant versus standard endocrine therapy. It brings a little more tolerable life to this pathway in terms of toxicity, but it also opens up inclusion because the patients in this study were not just PIK3CA-mutated, they also had AKT mutations and they had P10 alterations and loss. And so we're sort of widening that pot of how many patients are eligible in the second line space, which I think is great. When I see these alterations, I'm always a little bit concerned because I know that the drugs are harder on patients, but it's nice to have a meaningful option.

Dr McCann: It's also important to note that in CAPItello-291, the intention-to-treat population overall benefited, so patients who didn't have a PI3 kinase or AKT alteration or loss of P10 as well. And that's also true of everolimus, which I think is important to always include, but in the alpelisib trials, that medication was only shown to be beneficial in those with the PI3 kinase activating mutation.

Dr Kruse: I think that's so important as we design trials too, right? That having those patients, even though we think that the targetable alterations are more likely to show benefit, having the wild-type population, you never know what you're going to see, right? And we could miss out on really important clinical activity if we don't look.

Dr Wander: I think that's a great point, and probably, biologically, what's happening there is you have patients we can detect on targeted sequencing solid or liquid who have these alterations, but there are additional patients who may have pathway activation that we can't detect with currently available sequencing technology. So you may be able to see benefit in what we're calling a wild-type population, which is maybe a further subset of patients who have some activity.

We heard about these 2 drugs. We heard about some of the key toxicities in terms of hyperglycemia, some GI-related issues, rash. We talked about the fact that in SOLAR-1, and given the FDA approval for alpelisib, it's really just for the activating PIK3CA mutations. Whereas for capivasertib, it's for PIK3CA, plus P10, plus AKT, any of the above. Maybe we can do one more time what we did last time if we just go down the row. I think one of the key questions now is if you have somebody who's eligible for both, what are you doing in your clinic? Are you using alpelisib if it's PIK3CA? Are you using capivasertib for everybody because of what you were indicating maybe being a little bit more tolerable?

Dr McCann: In my clinic, I think because alpelisib has almost a guarantee of having diarrhea and rash and hyperglycemia, the tolerability of that medication is not as high as capivasertib, which is dose for 4 days on, 3 days off. So patients do still get those diarrhea toxicities, rash, potentially hyperglycemia, on capivasertib because that's just a side effect of inhibiting that pathway, but it tends to be a more tolerable medication.

Dr Lu: Yeah, same here. In my clinic, I tend to use capivasertib at its time, and given the more tolerable side effects and then the quality of life, it’s much better comparing with alpelisib. But I think alpelisib is certainly a very good drug, whether you can use sequencing, PIK3CA, another one. So maybe I'm saving this for the future. And now we have one more newcomer.

Dr Kruse: Yeah, I agree. I think the key with either of these drugs, whatever you pick, my more common utilization will be for capivasertib, but I think a lot of it is just prepping the patient for what they would experience. And we can do a lot in advance to make it more tolerable. I think there are a lot of patients that we identify hyperglycemia is going to be an issue and we might start metformin. For sure, antihistamines to prevent rash have been really helpful. I think many of these patients will know about diarrhea and how to manage it, but if they haven't had that issue and you prepare them in advance, you're just more successful.

Dr Wander: It seems like, again, we have consensus here on this topic that both are active drugs, it's good to have them. There's been a shift toward more use of capivasertib here based on this sense that there's maybe a little bit easier to manage toxicity profile in real world practice.

Of course, and this is probably the topic for an entirely different discussion, but we have not only next generation agents targeting the PI3K/AKT pathway, but we also have next-generation anti-estrogen agents, where we're developing combinations with these currently available agents. So we'll have new opportunities to maybe get away from the fulvestrant injections, have an all oral regimen that is more tolerable and easier for patients to take at home.

With that, let me thank you all for your comments, and thanks to the audience for participating as we're talking about these really important, widely used drugs in our clinical practices. We hope you'll join us for part 3 of the discussion, where we'll focus on the newest PI3 kinase inhibitor, inavolisib.