Sara Tolaney:
Hi, welcome to this program focusing on San Antonio updates with VJ Oncology. My name is Sara Tolaney, I’m a breast medical oncologist at Dana-Farber Cancer Institute and I’m joined by two of my incredibly wonderful colleagues, Dr. Sarah Sammons and Dr. Paolo Tarantino. Welcome.

Sarah Sammons:
Hi everyone. Happy to be here.

Paolo Tarantino:
Hi everyone.

Sara Tolaney:
So today we’re going to jump right in and we’re going to talk about a lot of the updates that actually happened, initially we saw in hormone receptor positive disease. And I think one of the key takeaways that we saw was that there are lots of strategies to think about when someone progresses on a CDK4/6 inhibitor. And one of the questions that was addressed is, could we use an AKT inhibitor in this sort of second-line post-AI population? And so we saw data from CAPItello-291, which had randomized patients to get fulvestrant with or without capivasertib. So maybe Paolo, I’ll start off with you. What was your main takeaway from this study and the findings that we’re seeing?

Paolo Tarantino:
I feel that this study fills an important gap that we have that is the second-line after CDK4/6 inhibitors, where we have seen the fulvestrant really underperforms compared to what we observed historically. And the PFS in most of the studies with only fulvestrant is around three months. And so showing that with a biologic drug we can achieve up to seven and more months of PFS. And also there was a positive trend in overall survival in this study, it’s very encouraging. Probably what we were not completely expecting is to see a benefit both in the biomarker-selected population, about 40% of the population, and also in the overall population. And apparently in the pathway non-altered, although there were some unknowns that were included. So I feel that we have to understand a little bit more about this biomarker non-altered, but overall it’s very important news and very intriguing data. What did you think Sarah, of this data?

Sarah Sammons:
For me, this population, about 80% of patients had received a prior CDK4/6 inhibitor, so this is one of the first randomized Phase III endocrine therapy combination trials that really enriched for a post-CDK4/6 inhibitor population and showed pretty substantial efficacy, so I think that’s important. Competitors to what this combination in the post-CDK4 space would be, are fulvestrant-everolimus. Well, we don’t have a study in the post-CDK setting with that combination. Or of course fulvestrant-alpelisib in a PI3 kinase mutant population. So when we’re choosing between capi-fulvestrant and a PI3 kinase mutant population or alpelisib-fulvestrant, I think it’s really going to come down to tox. And so I think probably we should point out some toxicity differences maybe between what we saw with capi.

Sara Tolaney:
What did you think, if you were to juxtapose the toxicity, which I realize we should never really do cross-trial comparisons, but if you’re thinking about rates of hyperglycemia for example and rash and you’re comparing alpelisib to capivasertib, what were your impressions of the differences in toxicity?

Sarah Sammons:
Sure. So there’s a bit less hyperglycemia, the overall rate of hyperglycemia in this trial was about 16% and most of it was low-grade, so certainly less than the 60-ish percent that we see with alpelisib. And in this trial they included patients with a hemoglobin A1C up to eight, whereas in SOLAR-1, they did not include those patients. So this would certainly be more of an option for patients where you were worried about hyperglycemia. There was a bit more diarrhea in this trial, all-grade diarrhea was about 70%, most of it was low-grade and something that we can certainly handle in the clinic with anti-diarrheals. So it’s still an endocrine therapy combination with some toxicity, mostly diarrhea, GI disturbance, some rash, stomatitis. But overall I think something that we can manage and will be a good option for many patients.

Sara Tolaney:
Yeah. No, I think it’s really incredible to see this agent have such robust activity, particularly in a post-CDK setting which was the majority of patients in this particular trial, with a little bit less tox than what we’ve seen with alpelisib, so I think more to come. So I think we do need to understand the benefit in the biomarker non-altered population a bit better. And hopefully once they get their ctDNA data and have fewer unknowns, hopefully that will help us tease out those differences.
So we also saw a lot of excellent data emerge about oral SERDs. So certainly we had seen data regarding elacestrant from the EMERALD trial previously, and are eagerly awaiting to see if this will get an FDA approval, hopefully in the very near term. But I think we’re a bit disappointed by the very modest benefit that was seen in the overall population and even in the ESR1-mutant population. And so there is an analysis done at ASCO really trying to tease out who those patients are who do derive long-term benefit from elacestrant. And so maybe Paolo, you can tell us what you thought of this particular analysis.

Paolo Tarantino:
I think it was very extremely helpful to see these analysis because it allowed to understand which is the population which might benefit the most of a monotherapy endocrine treatment like this, after progressing to prior CDKs and even other treatments. And I feel that this study and other studies presented at San Antonio showed that the population benefiting of this novel SERDs in this position is mostly patients that have ESR1-mutant disease and that derive prolonged benefits for prior treatment with CDKs. And we can see that for patients that have received CDK for at least 12 months, and the elacestrant achieved 8.6 months of PFS if they’re also ESR1-mutant, and this is very meaningful. Of course, it is not an extremely large population but I feel we’re going in this direction, to try to tailor our treatment based on the disease characteristics. And so in this case I really feel that this analysis will help us understand how to use this drug once hopefully it’s approved.

Sara Tolaney:
I totally agree with you. I think seeing that very steep drop-off in the curves in EMERALD makes you worry that a lot of patients are rapidly progressing. But then there are those people who are on for a really long time, and understanding who they are is really important because we don’t use very much endocrine monotherapy post-CDK. And so figuring out that it’s the people who actually were on their CDK for a long time and had an ESR1 mutation are the people who are really deriving the longer term benefit, and I think agree, very helpful once we get an approval to be able to help the select patients who may be the people who benefit. But we’re also seeing data about other oral SERDs, which is nice, particularly after I think a pretty disappointing ESMO, where we saw several negative trials, now we’re seeing a positive one which was exciting, and this was SERENA-2. So Sarah, what did you think of this data with regards to camizestrant?

Sarah Sammons:
I definitely thought it was interesting. I’m excited about the potential of this oral SERD. They did two different doses have camizestrant, they used 75 milligrams and 150 milligrams, and then they used fulvestrant as the control arm. And the median PFS was very similar with camizestrant 75 and 150. It was 7.2 months with the 75 milligram dose and 7.7 months with the 150 milligrams versus 3.7 months. So first and foremost, I love that there were two doses included. I know that that’s the FDA pushing us to do that and really pick the right dose, but I love seeing that. And I believe the 75 milligram dose is what’s moving forward. And again, we’re seeing a pattern, we’re seeing who is really benefiting from these drugs, and it is more looking like the ESR1 mutant population is really whom is going to derive the most benefit from oral SERDs.

Sara Tolaney:
And there were some unique toxicities with camizestrant. I don’t know if you could tell us a little bit about what you commonly see with SERDs, and then what you thought particularly of the toxicity with cami?

Sarah Sammons:
Sure. So when we’re developing novel endocrine therapies, or any therapies in metastatic breast cancer, we always have to get back to the basics. Until we cure metastatic breast cancer, quality of life in my opinion and my soapbox is as equally as important as trivial improvements in PFS. But overall this oral SERD is pretty well tolerated. This oral SERD does have a unique toxicity of photopsia, which is sort of very low-grade visual disturbances, were seen in about 20% of patients that were low-grade and temporary. And then they also saw very low-grade asymptomatic sinus bradycardia. So these are things that we have to think about when we’re using this drug as monotherapy potentially in the future, and certainly when we’re combining this drug with other novel agents.

Sara Tolaney:
I think it’s a good point, and especially now as these drugs are really trying to move into the early disease space, into an adjuvant population and potentially replace AIs, and people will be on these drugs for a very long period of time. I think quality of life certainly will be critical as we think about, again, moving it even earlier. So we’ve talked about some of these oral SERDs, like elacestrant, camizestrant, there are also other ways to degrade ER and there’s a different sort of class if you will of these kinds of drugs, being the PROTACs, and there was some data presented for ARV-471, maybe Paolo you can tell us what you thought of these data?

Paolo Tarantino:
So first of all, I think that this drug is a very interesting mechanism of action and kind of shows that we can degrade the estrogen receptor and achieve responses and activity with this novel mechanism of action. At the same time, I feel that it’s very hard to derive conclusion of this data because this was a very highly pretreated population and so it’s not really the population where usually you might think of single agent endocrine therapy. And so you can see that here in this Phase II trial, the VERITAC, ARV-471 achieved a medium PFS of 3.5 months in the 200 milligram dose, 3.7 months in a total population, up to 5.5 months in the ESR1-mutant population. And I think something interesting to see was that the compound seemed very well tolerated, but once again I feel we will need more data probably in a different setting, an earlier setting, to understand if there is a role for this drug. And hopefully also in randomized, I think to understand how it compares to current standard of care.

Sara Tolaney:
I think you’re right, this was sort of a unique trial because almost 80% of people had prior fulvestrant, about half the people had prior chemotherapy, so it was very late line. And I think what intrigued me was seeing a 50% CBR rate, in an ESR1-mutant population in such a heavily pretreated group of people, I thought seemed quite promising, and with the clean tox profile, I agree we need more data though. And so there is an ongoing randomized study comparing it to fulvestrant, and in fact a planned study combining it with CDK4/6 in the upfront first-line metastatic setting. So I think we’ll see more to come and have to tease out how these different ways of degrading ER pan out and what the right setting is for them.
So I think another question about thinking about strategies post-CDK4/6, we talked about use of an AKT inhibitor, we talked about oral SERDs, but I think one of the lingering questions we’ve had is, is there a role for continuing CDK4/6 inhibitors beyond progression? We had seen some data from MAINTAIN presented at ASCO, looking at the idea of using ribociclib predominantly in someone who had progressed on palbociclib, with also changing the endocrine backbone, so changing both the endocrine backbone and changing the CDK4/6. And in that setting, we did see the use of ribociclib as a continuation strategy was successful with an improvement in PFS, compared to just using endocrine therapy alone in that setting. But here at San Antonio, we saw data from our colleague, Erica Mayer who looked at really the question of continuation of palbo post-palbo with a switch in endocrine backbone, and this was the PACE trial. So Sarah, maybe I’ll turn it to you, and what were your thoughts with regards to these data?

Sarah Sammons:
I think this is critically important data because I think that people have been sort of doing this off-label and have had the question of if somebody has some maybe mild progression on AI palbo, and they’re tolerating palbo really well, can we just switch the backbone? Can we just switch them to palbo-fulvestrant? And this trial clearly answers that question for us. The answer is that we cannot. Continuing palbo-fulvestrant after progression on AI-palbo does not have any improved efficacy over just giving them fulvestrant alone, so that is not a strategy that should be taken.

MAINTAIN was an interesting trial. I think the question remains after palbo, ribo or abema, can you switch the CDK4/6 inhibitor and switch the endocrine therapy backbone? And that question will somewhat be answered in the Phase III postMONARCH trial which is ongoing. But in such a crowded post-CDK4/6 space now, this strategy becomes a little less appealing at least to me. But one of the most interesting things about this trial presentation I think was the triplet arm. So the actual very surprising advantage in PFS and potentially OS with the addition of avelumab, so an immune checkpoint inhibitor added to palbociclib and fulvestrant, which yielded a median PFS of 8.1 months. And I think this is signal finding and very interesting, and toxicity with other accommodations like this has been inhibitory in the past, so I think interesting and hopefully more to come there.

Sara Tolaney:
Yeah. No, I think this is a little disappointing because you’re right, I think many people were doing this in practice, it is an area where most people were getting palbo upfront and people were thinking about continuing it beyond progression. It’s hard because these are randomized Phase IIs, both MAINTAIN and PACE. And there are some caveats with that, right? I think in this case I was a bit surprised by the performance of the control arm with fulvestrant having a PFS over four months, and there were imbalances in the arms with the more endocrine-sensitive population being in the control arm, and more de novo patients, so you tended to see again better performance. And so I think it’s always hard to say this is definitive data but we’ll see more data to come. PALMIRA will report, looking at this question of palbo continuation.

And then I think a big question we’ve had is with regards to abemaciclib, right? So we’ll see postMONARCH, and then even the EMBER study looking at this question as well. So I think more to come, but I very much agree with you that at this point in time I would not use palbociclib after palbociclib, given the data that we have right now. So I think we also saw a lot of interesting data come out about antibody drug conjugates, and we do have post thinking about CDK4/6 and AKTs and SERDs, we start moving towards chemotherapy. And we had seen data at ASCO and at ESMO with regards to sacituzumab govitecan, a TROP2 ADC that we’ve already had approved in metastatic triple-negative disease based on the ASCENT data, but have now seen data in the hormone receptor positive space with TROPiCS-02 comparing saci to chemo of choice in a very pretreated population, so people with two to four prior lines of chemotherapy.
And we’d seen the PFS and OS data already presented suggesting improvements in PFS, and a little over a three month OS delta between the two arms. And so I think we’re just really pending approval of this agent. But I think one of the questions that continues to come up with ADCs is how to appropriately select patients, and are there biomarkers we should think about? With one question in this case being does TROP2 level impact benefits to sacituzumab, and should it be used to select patients for this agent? So Paolo, what did you think of these data, looking at TROP2, in the TROPiCS-02 study?

Paolo Tarantino:
I found these data very biologically challenging because of course when we think of antibody-drug conjugates we believe that the conjugate of course needs a target in order to internalize the compound into a cancer cell. But we are discovering that these agents act in a more complex way, in several ways actually, and this might be one of the reasons why in TROPiCS-02 the benefit of sacituzumab over traditional chemotherapy was seen regardless of TROP2 expression. And this was very clear, especially at the overall survival analysis, where even in patient with less than 10% expression of TROP2, there was an overall survival advantage. And so it really tells us clinically that we don’t need to assess for TROP2 expression, and so it’s good news because it means that we can provide this benefit in terms of our survival with sacituzumab for the overall population including the study.
At the same time, it tells us that we have probably to study antibody-drug conjugates more to understand what other components of the mechanism of action can be relevant in order for them to be active. For instance, internalization or bystander effect or any other means that can be enhanced in order to enhance their activity. And I think also extrapolating this, for instance to T-DXd, that we have seen that was very active in HER2-positive disease, in HER2-low disease, and there was a hint also in the HER2-zero disease. And so in putting together all these data, probably these ADCs might have an activity in the overall population, but for sure we need to study this more. And one thing that is exciting is that we’re bringing them in earlier lines and so it’s once again very important to understand how best to use them compared to traditional chemotherapy.

Sara Tolaney:
No, I think you’re exactly right. And maybe just sticking on this biomarker theme, maybe you could also tell us about the data that was presented from DESTINY-Breast04, with regards to expression or sort of central testing for HER2-low and how that correlated with outcomes. Because I think that’s been a major question that has arisen, is how to select people for T-DXd who have HER2-low disease.

Paolo Tarantino:
Absolutely. This was very complex because when T-DXd was approved for HER2-low, we had an approval for HER2-low metastatic breast cancer. But then we know that HER2-low is let’s say an evolving feature. A tumor can be HER2-low in the primary tumor and become HER2-zero in the metastatic setting, and the opposite way around. And so it was pretty challenging to understand which patient we can consider HER2-low. But then seeing the biomarker analysis from D-BO4 presented, really helped us understand that the population included in the trial was mostly enrolled based on archival samples or even primary tumor samples where HER2-low expression was detected. And the activity of T-DXd in HER2-low was confirmed, even if HER2-low was detected only on the primary tumor.

And so I feel that for this population of patients that don’t have the amplification of HER2, T-DXd can be thought of, can be used if HER2-low expression is detected at any time point of the disease. And this will help us use the drug in the clinic, but there are still many questions in the field that we need to answer. And hopefully DESTINY-Breast06, another Phase III trial will help understanding some of these questions. But also some work that we are doing that we need to do in the real world will help to understand if this evolution in HER2-low expression impacts the activity of T-DXd or not, and also what are the mechanism or resistance of T-DXd in HER2-positive and in HER2-low disease.

Sarah Sammons:
I just want to point out something really clinically relevant that that showed me. It didn’t matter for HER2-low patients if it was from the primary, the met setting, the time period. So whereas I had previously been re-biopsying some patients to see if they were still HER2-low, I will not do that anymore, and that will save cost and that will save patients undergoing a biopsy with potential risk and complications. So when I’m giving standard of care patients, the only patients I’m going to re-biopsy are those patients who were previously HER2-zero and I’m trying to get an indication to give them this drug in the met setting.

Sara Tolaney:
Yeah. No, it’s very helpful information. I think we’ll certainly need more data though about what efficacy is of T-DXd in someone who may have a recent biopsy that’s HER2-zero because we don’t actually have that data. But I very much agree with you that that’s an important clinical lesson for now, and we’ll see how this all evolves with time. So maybe just to wrap up, one final study sticking on the T-DXd theme is switching gears into the HER2-positive spaces, we did see updated data from DESTINY-Breast03, which had compared T-DXd to T-DM1, really in people who had previously progressed on taxane-trastuzumab, so people who are T-DM1-naive. And we had previously seen data with regards to PFS, but now we’ve seen updated PFS data and OS data. And so maybe Sarah you could tell us what your take home message was from this study.

Sarah Sammons:
Absolutely. So the updated PFS data by blind independent central review was reported and we saw a median progression-free survival of 29 months with T-DXd versus 6.8 months with T-DM1, so a four-time improvement which is absolutely remarkable. And then I think what we’ve all been wondering is, is this going to pan out to an overall survival benefit? And the overall survival in both arms was still not reached, which is great news for our patients living with advanced metastatic HER2-positive breast cancer, these patients are living for longer and longer. But there does seem to be a statistically significant improvement when T-DXd is given. And then this trial I think of mostly as the second-line setting over T-DM1.

Sara Tolaney:
Yeah, that’s really unreal. We’ve never seen a PFS like this in metastatic HER2-positive disease, even in the first-line setting, CLEOPATRA, it’s only about 18 months, right? This is crazy. It’s 28 months, it makes you wonder how T-DXd will perform in the first-line. And so I think more to come on this drug, not only moving in earlier I think, and then also moving it into the early disease space where there are studies ongoing. So I think it was a wonderful San Antonio, and thank you so much to both of you for this outstanding discussion. It was great to hear your takes on the data. Thank you so much.

Paolo Tarantino:
Thank you, Sara.

Sarah Sammons:
Happy Hanukah.

Paolo Tarantino:
Thank you everyone.

Sarah Sammons:
Thank you.

Sara Tolaney

Sara Tolaney reports consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Chugai Pharmaceuticals, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer.

Sara Tolaney reports research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Sanofi, Seattle Genetics.

Paolo Tarantino

Paolo Tarantino reports AstraZeneca, Daiichi Sankyo and Lilly.

Sarah Sammons

Sarah Sammons declares research funding to their institution from Astra Zeneca, Abbvie, Bristol Myers Squibb, Eli Lilly, SEAGEN and Sermonix; and consulting fees from Foundation Medicine, Astra Zeneca, Daichii Sankyo, Eli Lilly, Pfizer, Sermonix and Novartis.