Harold Burstein, MD, PhD, and Erica Mayer, MD, MPH, discuss the CAPItello-291, VIKTORIA-1, and STX-478 trials which were presented at the 2025 San Antonio Breast Cancer Symposium
We're gonna have a great discussion here about emerging targeted therapies for advanced breast cancer and leading this discussion is Doctor Erica Mayer, who directs our clinical research program in the Breast Oncology Center at Dana-Farber. Erica, what's happening in the space of targeted therapies? Thank you so much for inviting me, Hal, and um there's so much going on with targeted therapies. I wanted to review some of the really exciting data that we saw at San Antonio looking both at ways that we look for actionable mutations in cancers and also think a bit about some of the um really promising agents that are coming out, particularly those targeting the PI3 kinase pathway. So, um, to get started, we're going to begin looking at some, um, additional analysis from the Capitello 291 study. So, remember, uh, Capitello 291 is looking at the oral AKT inhibitor Kapivasertib in metastatic hormone receptor positive HER2 negative breast cancer. Now, remember, this is a registration phase 3 study that enrolled patients who had had up to two prior lines of endocrine therapy for advanced disease with hormone receptor positive HER2 negative disease, up to one prior line of chemotherapy. At least half of the patients had prior, uh, exposure to CDK46 inhibitor, and patients are randomized to get, uh, Kapivasertib with fulvestrant or, Placebo with Fulvestrant. Now we've already seen the primary data from the study demonstrating in both the ITT as well as in the AKT altered population, patients receiving the doublet of Capivasertib and Fulvestrant had a significant improvement in progression-free survival over Fulvestrant monotherapy with a hazard ratio of 0.5 in the AKT altered population. And this is what's led to the approval of Capivasertib in patients who have a mutation in the PI3 kinase pathway. Now, the challenge though is identifying our patients who have these mutations in their cancers and thinking about what is the best way to test for this. So we saw a presentation at San Antonio looking very specifically at how this was tested in the study population. Thinking about the question, what is the most accurate way to test? Is it through blood, through CTDNA, or is it through tissue? So this analysis looked at the 279 patients in the study who were found to have a PA3 kinase pathway mutation and focused on how those mutations were detected. Um, and we, in looking at those who had both tissue and CT DNA, uh, collected, it was shown that about 10% of the patients had these PF3 kinase alterations detected in CTDNA, but not detected in tissue. About 11% of the patients had the mutation detected in tissue, but not CTDNA. Now, drilling down on PA3 kinase pathway mutations, it was the P10 mutations that most commonly were discordant between the methods. So, the summary from this analysis was that first of all, um, it's very important to know the genomic status of our tumors in order to properly identify and apply the right targeted therapies. CTDNA is a very nice, minimally invasive way to look for these types of mutations, and this is especially important when we have a patient for whom getting enough tissue through biopsy is really not medically feasible. Um, we, we know that there is this discordance, and about 10% of the time we will find the mutation in cTDNA alone, 10% of the time in tissue alone. And so this really supports that when a patient has a new diagnosis of metastatic hormone receptor positive breast cancer, we actually want to test through both methods, both tissue and through CTDNA. Now, we also saw uh data at San Antonio and updated analysis from the Victoria One study. This study is looking at the new medicine gatatoliib, which is an intravenous inhibitor of the PAM pathway, PF3 kinase AKTMTOR. Victoria one is a large phase three study. It has two main components, um, a, uh, study one, which is for the PF3 kinase wild type patients, and a study two for the PF3 kinase mutated patients. We have not heard yet from study two. We have seen results from study one. Patients who entered the study had had prior treatment with endocrine, endocrine therapy for metastatic disease, but no prior chemotherapy. And, um, they were randomized to one of three arms. There was a triplettoliib, uh, palbociclib fulvestrant. There was a doubletattoliib fulvestrant and the control arm of fulvestrant monotherapy. Now, we saw primary results from Victoria one presented at ESO this year, demonstrating the superiority of both the triplet and the doublet over the monotherapy. At San Antonio, we saw additional analysis. Uh, first of all, we, Looked at, um, time to progression free survival based on time to progression on immediate prior therapy. So, did the duration of time on the immediate therapy have any implication on how well they did with the geolisib treatment? The answer was no. Whether it was 6 months, 12 months, 18 months or longer beforehand, all of those patients benefited fairly equivalently from the use of geolisib in combinations versus fulvestrant alone. And this was seen for both the doublet and, uh, the, uh, triplet. Um, there was also an analysis looking at bone metastasis status, um, whether there was any difference in benefit from getatoliib in patients with bone only disease or non bone only disease. Uh, the numbers were quite small for bone only, but in general, again, it was quite consistent. Patients who received the get a doublet or they get a triplet had a superior, uh, outcome compared to those who received fulvestrant monotherapy. Now, this analysis also looked at some updated toxicity, uh, results. Um, first, uh, looking at stomatitis. Stomatitis was a fairly frequent side effect seen with tatoliib with rates of about 70% or so. And this is despite the mandatory use of prophylactic steroid mouthwash in all of the patients. Importantly, we can see from this figure that in both the, um, uh, triplet and in, Doubt groups, the onset of the stomatitis was very early in the first week of treatment, and we can see the rates of stomatitis declined pretty rapidly. Now, whether that was due to dose holds, dose reductions, applications of additional supportive care, we don't know yet, but we can at least know that if we were treating a patient with this drug, we would want to be very ready and prepared for onset of toxicity earlier on in treatment. Now, um, additionally, there was analysis looking at glucose levels. Uh, agents targeting the PAM pathway do have risks of hyperglycemia, and in, uh, Victoria one, getatoliib did not result in clinically relevant hyperglycemia and no major changes in hemoglobin A1c. So, in summary, we see that in Victoria one, there was a significant improvement in progression free survival using the PAM inhibitorgetatoliib, um, in all patients, irrespective of prior duration of treatment. Or bone only versus not. We see that stomatitis was quite prevalent and happened early on, but hyperglycemia was thankfully not a major side effect. Now, just taking a step back, thinking about these, uh, P3 kinase pathway inhibitors, we can see that there are some key toxicities that occur across the spectrum with these agents, including hyperglycemia, diarrhea, mucositis, and rash. And these can make it challenging to use these types of drugs in our patients. So, what's the solution? Well, the solution is moving to the next generation of agents, which are the mutant-specific PI3 kinase inhibitors. These agents very precisely target the mutated PI3 kinase in the tumor cell, but spare the wild type PI3 kinase in our normal tissues. And it's that sparing that helps prevent the off-target toxicities such as hyperglycemia, diarrhea, and rash. There are two lead agents here that we are following, uh, a drug from a company called Relay called Zoviliib. Now it has a name. And a drug that came from Scorpion, now Lily, called tersulisib. Um, now, we did see at San Antonio, uh, with tursulisib, we saw results from the Piccolo one study, which is a phase 12 trial of, uh, terrsulisib, both as monotherapy and in combinations. Um, there were three cohorts looked at here, monotherapy in combination with fulvestrant and in a triplet with endocrine and CDK46 inhibitor. Um, first, in terms of activity, these were really fairly heavily pre-treated patients, and we can see from these waterfall plots that there was activity observed across the board using the mutant-specific PI3 kinase inhibitor, um, demonstrating the efficacy of the drug. And interestingly, the majority of the patients in the combination cohorts are still on drug, so we're seeing a nice level of efficacy. Now, importantly, in terms of toxicity, and I recognize there's a lot of data on this slide, um, there were toxicities seen. The most common included fatigue, nausea, all grade hyperglycemia was 22%, uh, some diarrhea, but rates of grade 3 toxicity were fairly low. Um, and, uh, for, uh, this included, uh, LFT abnormalities, fatigue, neutropenia, but honestly, these rates were really quite low. Um, and so we see that the, this new drug, um, uh, in combination was well tolerated, low rates of the incidence of Pia3 kinase class toxicity. So, really exciting and, uh, makes us, you know, feel enthusiastic for next steps. So, regarding next steps, we are moving on to the peak, study, which is a phase 3 trial of this agent in the first line setting with CDK46 inhibitor and endocrine therapy. So, a randomization to the triplet or, uh, a doublet with a placebo. And we also have the Rediscover study, which is looking at the relay agent with fulvestrant versus Capivasertib and fulvestrant in the pretreated setting. So, um, if either of these trials are coming to you or available near you, definitely please support these because we're really excited to move these agents forward in their development. So, in conclusion, we know that targeting the PI3 kinase pathway is of great importance for metastatic hormone receptor positive HER2 negative breast cancer. If we have a new, a patient with newly metastatic disease, we want to test by both tissue and CT DNA if possible, so we, um, can eliminate any discordant or missing any, uh, potentially positive results. Um, new PAM pathway targeting inhibitor, Such as tatolib are very promising, but the pan-targeting may introduce toxicity, and perhaps the next step forward will be the mutant specific inhibitors which will allow the right balance of the precise targeting and efficacy, but reduce or minimize some of those off-target toxicity effects. So that's a whirlwind of a few of the really interesting abstracts we saw at San Antonio. Erica, thanks a tour de force of PIC-3CA inhibition, uh, all at once. Let me just ask you a few things, based on your last set of slides there. Um, first of all, we have 5 commercially available drugs in this space everolimus, alpelisib, Cayassert, invaliib, getatoliib, uh, pending, I suppose. uh, didn't I say Cay? I thought I said Cay. Um, in any event, how do you pick one of those 4 available agents at the moment for a patient who has a known PICC-3CA mutation? Yeah, so, um, it, it has been a very busy space, and, um, something that, you know, first of all, requires that we are really good about knowing the genomic status for our patient and knowing who is a candidate for these drugs. Um, and I would also point out that Pia3kinase mutations are truncal, so they would be present in a metastatic biopsy, but they could also be present in the primary biopsy. So if we don't have metastatic tissue, you can go to the primary tissue to test for it. Um, Alpeisib was the first true, uh, Pietrikinase targeting agent, and so many of us use that when it was first approved a few years ago. Unfortunately, that agent does suffer from a fair amount of toxicity, particularly hyperglycemia. It's made it a little challenging in clinic. Um, many of us have rotated towards Capivasertib as an agent of choice, and it's an interesting drug because it's dosed 4 days on, 3 days off, which I think is a really neat schedule to help reduce the onset of toxicity just when patients are. Beginning to feel the toxicity, you're into the off days. Uh, but that drug does have risks of diarrhea and rash, and so we have to be mindful of that. Um, I tend to use it with a prophylactic antihistamine for rash and a very low threshold to add, uh, an antidiarrheal if they begin having diarrhea. Um, the, uh, gatoliib, I think, is an exciting drug, and, you know, we'll see what happens with that. And avaliib has a very specific role in the first line setting for patients who are, uh, recurring on adjuvant endocrine therapy and have endocrine resistance. And so it's used in a triplet with palbociclib. That drug does have a fair amount of hyperglycemia associated with it. And so if we're using that, we, um, I think it's helpful to make sure a patient has a glucometer, that they check their sugar every day, that there's good communication with the group, um, and using prophylactic metformin may also be helpful. Do you think there's really a difference between a patient whose tumor has progressed in the adjuvant setting on an AI versus those who progressed in the metastatic setting? I mean, I realize those are the labels, but do you think there's really a difference there? Um, I think biologically perhaps not, not that much, but, uh, you know, I think the sense is that the patient's recurring on adjuvant AI. It may be more driven by the PI3 kinase mutation as opposed to other resistance mutations such as ESR-1. Got it. So you made a very interesting point about the discordance between the primary tumor test or the, the tumor test and the circulating tumor DNA on a liquid biopsy. I confess I've gone almost exclusively to liquid biopsy. It's so convenient. It's so easy to get. Um, are you really doing both on a routine day to day basis? I am, mostly because I, I do think getting a metastatic biopsy to confirm the presence of metastatic disease and confirm the immunohistic chemistry is, is really very helpful, and I think it's helpful for a patient to have that pathologic confirmation that this is indeed happening. But, Agreed on that, by the way. I think that is important. Yeah, and, but when I am like calling IR and getting my biopsy set up, I'm sending my CT DNA that same day, cause it takes a couple weeks to come back and usually by the time the biopsy is back, my CT DNA is back and I can begin putting together my treatment plan. OK. In the last couple of slides, you showed, um, a couple of interesting developments. So, first, uh, if I read this right, the relay study is one of the first studies actually going to compare head to head, uh, one of these products versus another. So, that seems like a very important direction to go. And the second is that we're now seeing these combination studies. So we saw this in a novel 120, right, where we're doing endocrine therapy plus a CDK46 inhibitor plus or minus a targeted drug. Do you think in the years to come we're going to be talking about 3 or I suppose even 4 or more drugs all at once, and what's the rationale for that? Um, gosh, that sounds really complicated. Um, a rationale wise, we, I think we, we all agree that mechanisms of resistance in advanced cancer are, are very sophisticated and complex, and it's not just a single pathway that's driving resistance in the majority of cases, but it's multiple resistance pathways. And so applying agents that target these different resistance pathways may be more effective than kind of a single pathway approach. But I do think that it brings in additional complexity and getting back to navalissib, um, if you're monitoring for and managing hyperglycemia and you're monitoring for and managing neutropenia, and you're also doing your injection therapy, that's a lot for a patient to manage, and it's a lot for the provider team to manage. Um, I think that, you know, we want our patients to have an excellent quality of life and to, you know, do as well as possible. And so I, I personally have great interest in. Developing drugs that are as effective as possible but help to reduce all of these off-target toxicities so patients will do well but not be burdened by all the symptom management. I want to thank Erica Mayer for joining us with a magnificent discussion of targeted therapy. More coming to the clinic near you. Thanks, Erica. Thanks, Hal.
