Report Back from ASCO: What’s the Latest in Metastatic Breast Cancer
Welcome to this bonus episode of our MBC life podcast.We just finished the last episode of season 2, but our team is already working on season three. The premier episode will drop in September. In the meantime we hope that you will catch up on any episode you missed from the first 2 seasons. And we have a few bonus pods for you in July and August.
Our MBC life is a part of the metastatic breast cancer program at share cancer support SHARE offers many educational sessions for people living with MBC. We are thrilled to continue to highlight them The 2021 American Society for Clinical Oncology (ASCO) Annual Meeting was held virtually once more during the first week of June. Over the 4 days, pivotal data from trials and labs was presented from across the globe to continue to advance the oncology field and patient outcomes. A few weeks after the meeting one of our producers here on Our MBC Life Victoria Goldberg welcomed Dr Timothy Pluard to a SHARE webinar where he discussed information from ASCO. We are pleased to bring to you that conversation and catch you up on the latest in MBC research.
OVERVIEW
Introductions. (Jump to section)
HR+ MBC
Follow up to PALOMA-3 trial(Jump to section)
Follow up to MONALEESA-3 trial (Jump to section)
Mechanisms of resistance to CDK4/6 - CDK2 (Jump to section)
SERDs (Giredestrant, Amcenestrant) (Jump to section)
SERCAs (H3B-6545) (Jump to section)
SARMs (Enobosarm) (Jump to section)
HER+ MBC
SYSUCC002 Trial (Jump to section)
HER2 Low (trastuzumab deruxtecan, trastuzumab duocarmazine, ARX-788 and RC-48 (Jump to section)
TN MBC
The IMpassion130 Trial (Jump to section)
Sacituzumab ASCENT (Jump to section)
Victoria Goldberg
"Welcome to the webinar Report Back from ASCO: What's the Latest in Metastatic Breast Cancer." I am Victoria Goldberg. It's my distinct pleasure and honor to introduce to you our speaker Dr. Timothy J. Pluard.
Dr. Pluard:
Thank you, Victoria. So thank you all for joining and I appreciate the opportunity from SHARE to be able to bring you some of the updates from 2021 Amerocan Society of Clinical Oncology (ASCO) Annual Meeting this year. Going through ASCO is somewhat like going to the candy store. There's so much stuff there that you don't know where to start, more importantly where to stop.
This was an interesting ASCO. There wasn't really a stop-the-press study, but there was really an interesting inflection point, because, in part, we were looking back at studies that previously changed our standard of care. Now we're more mature.
We were able to learn a lot from some of the correlative work that went into those trials. And we'll talk some about that, but we also got to see a glimpse of some of the future with newer agents and newer strategies. And we'll go through that as well.
Dr. Pluard:
So we'll start, with the ER+ [group] and we did have a long-term follow-up on the outcome of the PALOMA-3 trial.
So just to refresh everyone's memory about PALOMA-3 . This was a trial of fulvestrant and palbociclib compared to fulvestrant and a placebo in patients who had had prior hormonal therapy. It was a unique population, because unlike most of the other CDK4/6 trials, which really looked primarily at chemotherapy naive patients, about a third of these patients had had previous chemotherapy in the metastatic setting. So the long-term follow-up showed, which was very reassuring, the improvement in overall survival and a similar improvement in progression-free survival. At about 18 months the group receiving fulvestrant and palbociclib started to see a significant separation in the survival probabilities, that actually increased in time and then maintained.
So at six years later there's still a survival advantage, and it's fairly significant in terms of the absolute value. It's about seven months in overall survival. And these are patients who are very early in their treatment journey. So there are a lot of subsequent treatments that can occur after the fulvestrant and the palbociclib.
We'll talk a little bit more about some of the analyses that were looked at in various subgroups of patients.
We talked about chemotherapy. This is one of the analyses that I thought was very interesting. It looked at the outcome of group of patients who had prior chemotherapy versus those who had not had prior chemotherapy. So the no-chemotherapy group shows a very similar impact compared to the overall population, whereas in the group, which is about a third of the patients in the study, who had had prior chemotherapy, there really didn't seem to be a difference between fulvestrant alone and fulvestrant with the addition of palbociclib. So this is potentially hypothesis generating. You could speculate on the reasons why this might be. Perhaps, those patients, whose physician chose to give them chemotherapy early in the course of their hormone receptor positive disease, felt that they had very aggressive disease or they had a high visceral disease burden. It may also tell us something biologically that those patients may have underlying genetic changes or molecular abnormalities within their particular tumor that makes them possibly unresponsive to palbociclib, but also unresponsive to chemotherapy.
So we don't have any data to try and explain this, but I thought it was a very interesting observation. One of the challenges that we've faced over the past years, and I think it's diminishing, is the early use of chemotherapy instead of endocrine therapy in patients who are ER+.
In general, unless there's visceral crisis (which is a subjective definition), but unless there is a visceral crisis, women with ER-positive disease should always start on endocrine therapy. Number one, with the addition of the CDK4/6 inhibitors, it's very effective and in some studies as effective as chemotherapy. Number two, it's certainly much less toxic, and the quality of life is better.
It is an ongoing continued education that the mere presence of metastatic disease in the liver does not necessarily equate to the fact that you should not have endocrine therapy as long as you know that that metastasis in the liver is still ER+. Those patients are still good candidates for endocrine therapy and CDK4/6 specifically in first line therapy.
Dr. Pluard:
So switching over to
MONALEESA-3, a similar study to PALOMA except with ribociclib. So this was a somewhat larger study comparing fulvestrant and ribociclib versus fulvestrant and a placebo, no prior chemotherapy in this patient population, and they could have had only one prior endocrine therapy for advanced disease. They could have had prior adjuvant therapy in the early stage setting.
And again, what we see is that the benefits that were reported earlier are persisting and are quite substantial. If you look at five years, there's a 15% relative improvement of 50% overall survival in the patients receiving ribociclib. This long-term data helps us ensure that we're getting patients started on CDK4/6 inhibitors early in the course of their disease, Ideally in first line. When the data first came out about the CDK4/6 inhibitors, and it was primarily based upon progression-free survival, there was a lot of discussion about, “Do you have to start upfront with the CDK4/6 inhibitor? Could you save it for later?” I think that this is really compelling evidence that long-term benefit for starting early is persisting. And so, in my mind at least, settles that question.
These are the takeaways. The first point, the improvements are now well-established. The second point is important. Part of the MONALEESA presentation was looking at the time to progression on the second line treatment, because there's been some concern that once you use the CDK4/6 in first or second line therapy then subsequent endocrine-based therapies are less likely to be effective.
And so when you combine the progression-free interval on the CDK4/6 with the progression-free interval on their second treatment, it clearly still favored utilizing, in that case ribociclib upfront. So the third point was an analysis from PALOMA-3, looking at the impact of various mutations on the efficacy of palbociclib in combination with fulvestrant specifically. They looked at the presence of the ESR1 mutations, PIK3CA mutations, or TP53 . Almost half of the patients in the PALOMA-3 trial had mutations in ESR1 . So it was very meaningful. data. And what was found and true in all three mutations is - yes, the presence of one of those mutations is prognostic in that the prognosis is less than if you did not have the mutation, but the predictive value, and that is, that even with a mutation you're going to benefit from the treatment. In this case, the CDK4/6 inhibitor was still present despite the mutation. So even though the outcome with or without CDK4/6 inhibitor was below that of those without the mutations, they still benefited from the CDK4/6 as compared to placebo or endocrine therapy alone. That was very useful information to have, and we already talked about the lack of benefit from the chemotherapy.
Dr. Pluard:
We think about the estrogen receptor and how Cyclin D-Cdk4/6 are controlling the growth of the cells. It's a checkpoint. they control whether the cell goes into the growth phase of its life cycle. And so because we're trying to understand what are the mechanisms by which these cells become resistant and the treatment loses its effectiveness, there was some data presented. And it can be really one of two things, or one of two primary mechanisms, you can become resistant to the CDK4/6 inhibitor, or you can become resistant to the anti-estrogen agent that's in the combination. It is important to understand which of those it is in each individual patient, if possible.
And so we've already talked about some of the mutations in the estrogen pathway: ESR1, PI3K that can impact, but we also have mentioned p53, and then there was a number of studies looking at different signatures of resistance in this population. There's somewhat of a convergence around the Cyclin D-Cdk2 as a primary mechanism of resistance to CDK4/6 inhibitors, because they have the potential to directly impact the final step in the pathway.
So there are inhibitors of CDK2 in development (e.g. CDK2 inhibitor PF-07104091, recuiting P2 study NCT04553133) and hopefully we will start to see these emerge into early stage clinical trials and to the clinic at some point. We had hoped that, perhaps, the CDK4/6 inhibitors in combination with endocrine therapy would reduce the development of ESR1 mutations, but what was seen in the trials is that they are increased. Even in the presence of CDK4/6 inhibitors, perhaps, it slowed it, but it didn't eliminate the mutations in ESR1 as an escape mechanism for these tumors
Dr. Pluard:
Okay. So now switching gears to look forward. We had some very interesting presentations about emerging endocrine agents. There is a class of oral SERDS (selective estrogen receptor degraders). Fulvestrant is the SERD that's clinically available right now, but as everyone knows, it's an intramuscular injection monthly and an oral SERD would certainly be desirable replacement or improvement.
There are a number of them in development, in testing, and in clinical trials. We saw data on two of the SERDS (Giredestrant and Amcenestrant in Phase 3 AMEERA-5 trial ) and then a new class of drugs SERCAs (selective estrogen receptor covalent antagonists). H3B-6545 is an example, which we'll talk about here in a minute.
And then, a new class really, are the Selective Androgen Receptor Modulators (SARMs) and, Enobosarm was presented as well.
So here is the Giredestrant 1a/1b trial This was a patient population who had less than two lines of therapy in the metastatic setting.
And they were testing various dosing levels. But if you look at the population, it's fairly early, although two thirds of the patients had CDK4/6 Inhibitors and almost half had ESR1 mutations. There's a fairly good response rate in these patients who had had previous endocrine therapy. So this shows a promise, and later stage trials are already ongoing with giredestrant.. It's very well tolerated. Activity was seen whether there were ESR1 mutations present, and in patients who had prior endocrine chemotherapy or CDK4/6 inhibitors. The dose that they elected to move forward with is 30 milligrams. So hopefully we'll be seeing more trial results with this agent moving forward as a mono-therapy or in combination with CDK4/6 inhibitors.
Dr. Pluard:
More on H3B-6545 , so H3 Biomedicine presented a Phase two expansion of their Phase 1b trial, this is a population that was more heavily pretreated. They'd had a median of three prior therapies in metastatic disease. So this was really fourth-line therapy with an endocrine agent. So including 62% of the patients having an ESR1 mutation, 80% had previous aromatase inhibitor, 84% CDK4/6 inhibitors, and over 70% fulvestrant and 50% chemotherapy. So this is a fairly advanced patient population. Drugs seem to be fairly well tolerated, mild GI upset, a low incidence of anemia and a rather unique toxicity to endocrine agents - bradycardia or slowing of the heart rate. For the most part it was asymptomatic and patients weren't aware of it or impacted by it.
And the results in this population, again on average fourth line therapy, there was an overall response of stable disease for 6 months or 24 weeks. The progression-free survival of 5.1 months is certainly encouraging for a late line endocrine therapy where half the patients had previously had chemotherapy. One of the more interesting observations is since there were so many patients with ESR1 mutations, they were able to look at small subgroup that had a clonal mutation Y537S. This specific mutation seemed to do better with H3B-6545 than the population as a whole. Numbers are small. So it's hard to know how much to take from this, but it was compelling enough that the trial has been amended. And now they are enrolling a cohort specifically with this mutation.
And there may be chemical properties of H3B, which make it more effective in this specific mutation, but it also had activity in other ESR1 mutations that was similar to the group as a whole. So some encouraging results from this new class of drugs, for sure.
Dr. Pluard:
I'm switching gears here a little bit. We're switching into HER2 mode. This is a study that was presented from Chinese colleagues. This is sysucc-002 trial.
And this trial was asking the question of those patients who had had ER+/HER2+, comparing endocrine therapy to chemotherapy, with both in combination with trastuzumab. So at the time they did this study pertuzumab was not available. Basically they're asking the question, “Can we treat patients with endocrine therapy in combination with trastuzumab as opposed to moving directly to cytotoxic therapy in the first line also in combination with trastuzumab?”
And interestingly enough, this is designed as a non-inferiority trial, which failed to actually meet its primary end. The actual data suggests that the chemotherapy group was not clearly superior to the endocrine therapy group and they didn't specify the precise endocrine therapy that was utilized. There was some discretion of the treating physician, but it was in combination with trastuzumab
And again, when they looked at overall survival very similar for the endocrine therapy versus the chemotherapy in combination with trastuzumab.
So the trial is limited because it didn't compare to the current standard of care at least in the US, which would be trastuzumab, pertuzumab and a taxane like Taxotere in the registration trial (CLEOPATRA), For CLEOPATRA we have long-term follow-up that Dr. Swain presented at seven years, showing that 37% of patients were still alive after that first line therapy.
So that's a pretty high bar, but I do think that this provides additional evidence that non-chemotherapy regimens are realistic treatment options in this population. If you take the data from monarcHER, which looked at the combination of fulvestrant and abemaciclib, one could ask the question about adding abemaciclib to the endocrine therapy to lead to even better outcome in that arm. But I think this really gets to the point that we need to personalize our treatments in shared decision with the patient, because certainly endocrine therapy is less toxic.
If patients are not terribly symptomatic or asymptomatic from their metastatic disease, perhaps, a treatment regimen utilizing endocrine therapy with trastuzumab, which will have far less in the way of toxicity would be preferable, and then reserving the chemotherapy regimen for the later lines of therapy, when necessary.
Dr. Pluard:
So I'm going back to endocrine therapy now keeping everybody on their toes. We were talking about enobosarm which is a selective androgen receptor modulator (SARM), and historically, androgens were widely used when we had very few endocrine agents beyond Tamoxifen.
They were widely used in the treatment of ER+ BC but they're not very well tolerated, because of the androgenic effects, so they fell out of favor when aromatase inhibitors, came into the clinic. So this is a new class of drugs that modulates the androgen receptor, but it doesn't have the same androgenic off-target effects, of hirsutism and some of the testosterone-related side effects. And so they looked at ER+ patients, and they stained for androgen receptors, which are present in about 90% of ER+ patients.
And they used a cut of 40% staining and looked at the response rates based upon that. And for those patients who were above 40% AR staining, they had a 50% overall response rate, almost an 80% clinical benefit rate, a really significant effect in these patients, all of whom had been previously pretreated with anti-estrogens.
The take home message was that all the responses were seen in patients with ER+ tumors, that cut point of 40% was considered optimal to distinguish who would derive benefit. And there is now a Phase 3 randomized trial ARTEST comparing enobosarm to examestane in patients who've progressed on a non-steroidal AIs, namely anastrazole or letrozole, faslodex and a CDK4/6 inhibitor.
I think this is going to be a very interesting trial, because if what has been seen in the early trial is recapitulated, this may provide yet another anti-estrogen strategy to utilize before needing to go to chemotherapy.
Dr. Pluard:
Okay. So now I'm switching to triple negative. There was an exhaustive analysis of the tumor specimens that were obtained in the IMpassion130 trial, and I'm only going to talk about part of it. So just to remind everybody IMpassion130 was comparing atezolizumab plus nab-paclitaxel (Abraxane) versus placebo plus Abraxane alone, looking at progression-free survival and overall survival in just over 900 patients.
And again, if you look at the progression-free survival, there's a significant improvement of 1.5 months in progression-free survival, but more impressive was the seven and a half months improvement in overall survival in the patient population that was PD-L1 positive, based upon the SP142 assay.
So one of the analyses they did, was looking at the particular subtypes of triple negative breast cancer. We define triple negative breast cancer by what it's not, understanding that it's not a homogeneous group of tumors, and there've been a number of different categorization strategies.
This is one that's based upon molecular subtypes and is widely utilized The four subtypes: BLIA (basal-like immune activated), BLES (basal-like immune suppressed), LAR (luminal androgen receptor), and MES (the smallest group)
Basal-like groups comprise the vast majority of triple negative cancer. The expression of PD-L1 is much higher or the number of patients with PD-L1 expression, I should say, is much higher in the basal subtype that's immune activated versus the immune suppressed basal subtype and the other two.
And so what is very interesting is that, when you look at the PFS, based upon the molecular subtype, in the basal-like immune activated subtype, that there's clearly a significant difference in those patients who received atezolizumab than those who did not, there's a slight difference in this population but really not nearly a significant, and really not much in the other groups. So if this potentially identifies a way that we can go beyond PD-L1. And potentially identify those patients who are most likely to benefit from, for example, atezolizumab from this trial, and this analysis may help explain differences between trials, because these relative populations could be potentially different between trials and might explain some of the somewhat conflicting results that we saw with IMpassion131. So very interesting work there.
The other interesting analysis they did is they looked just at the presence of the CD8 T-cells. Those are the effector T-cells of the immune response. And so they characterize them as inflamed, which meant the immune system was pretty much throughout the entire system with CD8 cells, or they were excluded, they were there, but really on the outside of the tumor or it was an immune desert, there were no, ITLs to be seen. When you look within these specific subgroups in terms of their PD-L1 positivity, it's much higher in the inflamed group, still significant in the excluded group, but absent in the desert group for the most part, very small percentage. How does that translate into the effect on patients? Well, if it's inflamed, if your immune system is already there in place and actively working against the cancer that adding PD-L1 is likely to provide significant benefit, some benefit if the cells are there, but not actively into the tumor and very little benefit, if any, when there are no immune cells present within the tumor. A very interesting way of identifying or enriching, , for the patients who are most likely to benefit from these therapies.
Dr. Pluard:
So just very briefly on sacituzumab in triple negative breast cancer. Sacituzumab was approved as third line therapy in triple negative breast cancer. It's an antibody drug conjugate targeting the TROP2 receptor on triple negative breast cancer cells. And this was an analysis that was presented of the Phase 3 ASCENT trial.
That was the confirmatory trial leading to its approval. And they looked at the 65 patients in the trial who relapsed early, less than 12 months after completing their neoadjuvant or adjuvant chemotherapy and had received only one prior treatment in the metastatic setting. So essentially, you could consider their adjuvant chemotherapy as a line of therapy, which we often do if they relapse less than 12 months after completion. So very interesting results and quite honestly very similar to what was seen in third line that compared to treatment of chemotherapy of physician's choice, that sacituzumab may have had a much higher overall response rate, progression-free survival, and then more than doubling of the overall survival.
So I think that this just highlights the need to be aware that in this population that has a relatively poor prognosis, identified by their early relapse, that sacituzumab should be used earlier than their third metastatic line.
Dr. Pluard:
Okay. Now I'm going to finish up and close with HER2 low, which is really an emerging new breast cancer subtype that I think is going to have significant implications in our treatments for metastatic breast cancer, moving forward. We used to think of when we do HER2 testing, It's initially done by immunohistochemistry scored 0, 1, 2, or 3+ If it’s 3+ you are HER2+ clinically. if it's 2+ then you get FISH testing and if that's positive, then you're positive.
And we used to say that everything to the right of this is HER2-, and there was no benefit to HER2 targeted therapy. However, we now have some evidence that with newer antibody drug conjugates patients who are IHC 2+ and FISH negative or IHC 1+ may benefit from treatment with some of the HER2 targeting ADCs.
So just so everyone understands a little bit about what we're talking about when we talk about antibody drug conjugates. The concept is to take an antibody that recognizes an antigen on the cancer cell so that it will basically draw the antibody to the cancer. And then to that antibody is linked a payload, which is typically a cytotoxic drug.
And so in the initial concept the antibody drug conjugate would bind the antigen on the cell, be internalized. Then the linker that is holding the drug payload to the antibody would be dissolved. The payload is released and the chemotherapy is inside the cell and kills the cell.
That was the first-generation of antibody drug conjugates. And you can think of Kadcyla as the prototype for that. With improvements in technology we've now been able to get more payloads. So for drug payloads is probably about what Kadcyla carries now some of the newer antibody drug conjugates are carrying double that.
They're delivering more of a payload to the target and also the chemistry behind the linkers and what causes the release has changed. And so they can be hydrolyzed, double or cleavable, and they can actually be in the microenvironment of the tumor, which tends to be more acidic.
There are some linkers that can be broken. And if there are tumor cells that don't have the target antigen they're killed by what we call a bystander effect, which can also happen when this cell dies. And the payload is released out into the tumor microenvironment. In terms of the HER2 ADCs, Kadcyla was the prototype, approved nine years ago or so, and trastuzumab deruxtecan INHERTU has shown activity and so did trastuzumab duocarmazine (SYD985).
So we know that INHERTU has already completed enrolling at Phase 3 trial in HER2 low patients, and hopefully those results will be forthcoming soon, and the TULIP Phase 3 study with trastuzumab duocarmazine just recorded their top-line positive results in a press release right at the time of ASCO. So I suspect we'll see those this fall or at San Antonio. And then there are quite honestly multiple others, but there was data presented on two other HER2 ADCs ( ARX-788 and RC48) which I won't go in to for the sake of time.
But the impact of this is significant. Looking at the prevalence of HER2 low in various breast cancer subtypes, whether they're hormone receptor positive, or hormone receptor negative. It’s highest in the hormone receptor positive. It's 50% of the non-HER2 amplified population is HER2 low. That’s a very sizeable population of patients who could potentially benefit from HER2 targeted ADCs if they are HER2 low. We're going to be hearing a lot more about the HER2 low subgroup.
