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 final part of this discussion, our experts explore the data on the newest PI3 kinase inhibitor, inavolisib, from the INAVO120 trial.

Transcript:

Seth Wander, MD, PhD: Welcome back to Oncology Learning Network. My name is Seth Wander from Massachusetts General Hospital in Boston. It's my pleasure today to be joined by Dr Kelly McCann from UCLA, Dr Janice Lu from Northwestern, and Dr Megan Kruse from Cleveland Clinic.

Welcome back to the third part of our discussion regarding PI3 kinase pathway inhibitors in hormone receptor-positive metastatic breast cancer. We'll now turn our attention to the newest agent in this field, inavolisib.

Megan, tell us a little bit about how inavolisib compares to alpelisib in terms of the drug itself.

Megan Kruse, MD: These drugs are both PI3 kinase inhibitors. They're specific for the alpha subunit, they actually are both continuously dosed oral medications. So many times when you're thinking about them on the surface, they look very similar. But when you think about the mechanisms of action, the way that inavolisib is a little bit different is that it is also a degrader of the PI3 kinase in addition to being an inhibitor. And I think that translates into some of its activity, clinically.

Dr Wander: Great. Kelly, tell us a little bit about the INAVO120 trial, which we recently saw results from and has really changed our practice. How was the study designed and what would you say are the key takeaways?

Kelly McCann, MD, PhD: Sure. The patient population who were enrolled in this had to have a PI3 kinase mutation, first of all. Secondly, they were patients who progressed on their adjuvant endocrine therapy or progressed within a year of completion. So this is a very high-risk patient population who is going on to their first-line therapy with fulvestrant, palbociclib, plus or minus inavolisib.

Dr Wander: Great. And what were the key sort of clinical outcomes from that?

Dr McCann: There was a median progression free survival for the triplet therapy versus the doublet therapy of therapy of just palbociclib and fulvestrant.

Dr Wander: Great. And Janice, what do you think in terms of the trial? And I know all of us are still about to get used to using this drug, because the FDA approval was so recent and I think we're all seeing our first patients and we'll talk about how we're identifying them. But from the trial, what do you think were the key toxicity takeaways in comparison to what we discussed earlier?

Dr Lu: The FDA approval was 10/10, October 10th. It’s really just 2 months ago. I think the key takeaway is the progression-free survival: 7.3 months versus 15 months, that's a significant increase of progression-free survival, in favor of the triplet in combination with inavolisib. And also the patient population certainly is a very aggressive disease progression. Most of the patients, up to about 50% of the patient, have more than 3 or equal to 3 visceral disease at different sites. And also, about 45% of patients have liver metastases as well. This is a group of patients with aggressive disease, primary and secondary, progression on AI or just within about 12 months finishing AI.

The key takeaway is that this is something that works well and this is something in terms of toxicity is also better tolerated in alpelisib.

Dr Wander: In what ways, in terms of the toxicity comparison?

Dr Lu: Yeah, in terms of hyperglycemia, it's only like in the single digits, compared to with alpelisib at 37%. However, the inclusion criteria is different. Alpelisib included patients with hemoglobin A1C of up to 8, and then this trial is up to 6 only. Also, with rash is manageable, single-digit, and there's no grade 3 or 4 rash at all for this group of patients who are enrolled in the study. And also they were all manageable. With symptom control, grade 3/4 all got resolved. This is something it appears patients will tolerate it, especially for grade 3/4 toxicities.

Dr Wander: Great. Megan, I'll start with you, but I might ask everybody for their thoughts on this, and we don't have to stick just to inavolisib. We've been talking a lot throughout our discussion today about hyperglycemia as one of the key issues, and I think the point Janice just made about slight differences in the inclusion criteria for these studies could have had major impacts on the grading and the frequency of this really key toxicity for the pathway.

Megan, in practice, for the whole class, how are you screening for and managing hyperglycemia? If somebody who's watching us today has a patient that’s PIK3CA-mutant, they're going to start them on one of the above agents that we've been talking about, what's your protocol in clinic?

Dr Kruse: This is where we really put our internist hats back on, right? We just need to watch these patients very closely. And many times we will have bloodwork for them leading up to this, where we have some sense of what their typical blood sugar levels are. But if you don't already have that information, you definitely want it before you get started: fasting blood sugar, a hemoglobin A1c. And if there's any hint that they either already have diabetes or they have impaired fasting glucose, those are patients that I'm connecting with their PCPs, sending them to endocrinology, and probably have metformin at the ready, to help with that insulin-sensitivity.

Certainly, once they start on the drug, frequent fasting blood sugar monitoring is important. And I think the frequency of that is going to depend on the patient and what kind of issue you're running into. For many patients on these drugs, metformin will be enough, thankfully, lifestyle and metformin. But there are a number of patients that you're going to need additional help. I think we try to, for quality-of-life reasons and for mechanistic reasons, avoid insulin in these patients. Many times, that's when I'm reaching out to an endocrinologist. If I need an agent on top of metformin, I'm referring them on. It just is a very close monitoring, a lot of communication and reaching out to colleagues for help.

Dr Wander: Kelly, any thoughts on that? Is that your practice as well in terms of how you're starting and what kind of frequency of monitoring for sugar?

Dr McCann: That's exactly what I do, too. As Megan mentioned previously, it's all about setting expectations for your patients and letting them know what could happen and how you would manage it. With alpelisib, I let them know that you're going to need to have a long-acting antihistamine to prevent the rash. You're probably going to be taking metformin, less of an issue with inavolisib, but again, those patients weren't high risk for developing severe hyperglycemia. And then for diarrhea you need to be able to manage that, and the patient needs to be able to anticipate so that they can self-manage at home. Because with oral medications there's a lot more self-management and not so much those patients coming in for IV chemo and having your nurses do a lot of that management.

Dr Wander: One question that that always comes up in clinic, and I'm not sure if any of you feel strongly one way or the other, but a dietary adjustment. Janice, in addition to all of these things, your patient comes in and says, "Okay, I'm worried about this. Do I change my diet?"

Dr Lu: We do have dieticians, so I do refer to them to the dieticians for the whole discussion. I practice in a very similar way, like Megan and Kelly here: expectation and anticipation and how to manage themselves and tell them the data, that with inavolisib the patients don't have grade 3 and 4 after the proper management. This is something, in a way, it's a comfort zone for the patients as well. And then rash, diarrhea, and also hyperglycemia. I have a very extensive conversation with them, and also, diet for rash and mainly for diarrhea. Probably not to eat something initially to start with and something easier for you to get diarrhea. And then I do have a very good conversation with them about this.

Dr Wander: How about either of you? Do you have any strict things about diet or recommendations?

Dr Kruse: It's so hard, because I feel like, for quality-of-life purposes, the last thing we want to do is restrict what our patients get joy from. And it's not like that they should be eating cupcakes for breakfast. But, at the same time, I think it's important to tell them “you likely will have these abnormalities resolve once you're off the drug.” Now that may not be entirely true, if they're on the borderline of diabetes and we push them there, but for patients with normal glucose going in, we expect this toxicity, and it will go away. And we hope they're on the drug for a long time and that we're dealing with this for a long time because it means their cancer is controlled. But it's nice for them to know that we're not sending them out of this treatment with both metastatic breast cancer and type 2 diabetes.

Dr Wander: I think that's a really important point. It's not like immune therapy where you can get thyroiditis and be permanently on thyroid replacement, or pancreatitis or something like that. Do you have any other thoughts on lifestyle things that come up? In LA, right, do you get a lot of questions like this?

Dr McCann: I have a very healthy patient population to start with in general. And I do talk to them to some extent about what makes your blood sugar go up. But just like with Megan, I don't tell them they absolutely must stick to a diabetic diet.

Dr Wander: Great. And Janice brought up this really important point. This is a really difficult to treat patient population. Even though we're talking about ER-positive metastatic disease and we're not often phrasing it the way I'm about to phrase it, this was really a critically important unmet need here. This is a relatively small population of patients who had upfront resistance to their aromatase inhibitor, their adjuvant tamoxifen. These are your patients who are on adjuvant therapy or shortly after stopping adjuvant therapy, they’re coming in. We really would struggle with these patients in the recent past. I think this is a hugely important advance, but it also now brings up the question of what are you going to do after? And this is a new question for us. This is the first time we've used a triplet regimen in the first-line setting.

Janice, I'm curious what your thoughts are. Now you're going to have this patient population. It's a rare subset, and then it's about 40 % within that who will be eligible for the inavolisib, based on having the PIK3CA alteration. We're going to put them on this drug. What are your thoughts on what you're going to use next after that?

Dr Lu: Yeah, that's a really good question. We don't have enough data or sufficient data at this time. So we put all 3 great drugs all together, get a fast car instead of slow car to start with. And so what do you do next? And then, but I think post-PIK3CA treatment, just like a post-CDK treatment, is it going to work or not with capivasertib? We don't know about this. So this is a question that is very important to ask and then see the sequential treatment.

And also, I'm using different kind of CDK4/6 inhibitor. The trial used palbociclib to start with. And how about ribociclib? And then abemaciclib, we know there is a survival benefit. And then I know that these trials are being at least planned or to be started. So I think that will probably help us a lot about inavolisib, plus CDK, post-CDK, switching CDK as one option, and switching endocrine partners probably is another option. Fulvestrant to switch back to AI is tough, because patients failed usually on AI already at the time. But maybe you can switch to a different kind of AI. This is not kind of up in the list of the treatment, but something to consider as well.

And versus switching to other treatment, totally different treatment. The second-line therapy looking for any biomarkers and other kind of mutations, like ESR mutation. This is the time you can get acquired mutation and then using monotherapy with elacestrant, versus adding CDK, their study ongoing now, ELEVATE trial, and we have a trial as well. So, these are my other options versus switching to, like Kelly mentioned, everolimus. This is something also is an option in CDK, post-CDK, with fulvestrant. So, these are all options. And ADCs as well, down the road.

Dr Wander: I think the point you made about sequential therapy within the pathway is a really important unmet need to answer that question. We have some preliminary data from phase 1 experience with earlier generation PI3 kinase inhibitors, that P10 and AKT can be resistance mechanisms. And now we have capivasertib, and we have other inhibitors in development. So biologically, hypothetically, you could maybe rechallenge a PI3 kinase-resistant patient with an AKT inhibitor, if they had acquired a P10 or an AKT mutation. I think that makes biological sense, but I don't think we have any data for that, even retrospective data. So we're actually starting to try to generate that data and then validate that in laboratory models. And I think that would afford an important opportunity. But, nobody on any of these trials had prior exposure to other agents within the pathway, these are all developed in parallel, right?

Dr McCann: We have the added complication of now that we have ribociclib and abemaciclib, so approved in the adjuvant setting, that those patients wouldn't have been included in this trial because we didn't have those approvals yet. That’s also another consideration.

Dr Wander: That’s another great point, which we had, this trial was designed to look at those high-risk hormone therapy-resistant patients. Now we're going to have high-risk CDK- and hormone therapy-resistant patients, and it's going to feel a little strange to rechallenge them with palbociclib as part of this regimen.

Megan, with that in mind, what do you think is the future here? Where are we going now that the sand is shifting under our feet with the adjuvant regimen, and we have triplets in the first line? What do you see in the next sort of 2 to 5 years?

Dr Kruse: Yeah, I think it's just a super dynamic space. And I think we really have to, as a community, drill down on some of the heterogeneity of these populations and maybe looking separately at the patients who have really great responses to targeting of the PI3 kinase pathway and those that don't. Maybe grouping those in 2 separate categories in terms of future trial inclusion criteria.

I think the other part here is really getting a sense of how much do we know about the endocrine resistance? How much can we salvage that with drugs like fulvestrant? So as you said, everything we're talking about today is in combination with fulvestrant. How do novel oral SERDs [selective estrogen receptor degraders] that may be more potent change that? Some of our other anti-estrogens that are coming down the road, like PROTACs [proteolysis-targeting chimeras] for example, does that change things? We're going to be faced with a lot of active drugs and the need to combine them without the data to combine them. And I think that's actually the hardest part, as we talk to patients. Because our inclination is going to be that we find alterations that we have something to do, but we don't have the data to back up all of those decisions.

And then, I think the ADC story is going to continue to evolve right now. I'm very, very excited about antibody-drug conjugates and all in this space. And I think as you were talking about these resistant patients, I was thinking, you know, if their biology is super-aggressive when they come out of targeting the PI3 kinase pathway, ADC is like what I'm going to next. And so understanding what that sequencing look like, do we get those wonderful responses to ADC after we do this more aggressive triplet therapy? The next few years are going to be really interesting as we watch it play out in the real world.

Dr Wander: We'll have you all back and we'll talk about that as we have more data coming coming back in. Let me just summarize now. We have new first -line data for this high-risk population of endocrine-refractory patients. If they're PIC3CA mutant, we have an FDA approval, and we can now offer them triplet therapy in the first metastatic line with fulvestrant, palbociclib, and inavolisib. And it was great to hear from you all about the toxicity profile, what kind of patients we're going to be using this in, what the future directions might be moving forward from here.

This concludes our discussion series. Thank you all for participating. I really enjoyed hearing from you and learning about all these new things. Please check out www.oncnet.com to catch the rest of this discussion, as well as other updates related to patient care and oncology. Thank you.