Report back from SABCS
Welcome to this bonus episode of Our MBC Life. Our team is currently working on season 2 and we are excited. The premiere episode will drop on March 1. While we do that, we hope you catch up on any episodes you missed from Season 1. We will have 3 more bonus pods for you in January and February.
Our MBC Life is a part of the metastatic breast cancer program at SHARE Cancer Support. SHARE has many programs to support women living with MBC including the Talk METS Helpline, several virtual support groups, and educational and wellness programs. We are thrilled to highlight some of those programs in January. It feels like a lifetime ago, but just a few weeks ago the world's largest breast cancer conference, the San Antonio Breast Cancer Symposium, was held. Just after the symposium SHARE welcomed Dr. Neil Iyengar from Memorial Sloan Kettering to a webinar where he shared information from SABCS highlighting both early-stage and metastatic research. We are pleased to have that conversation to start the year and catch you up on the latest in MBC research.
Christine Benjamin, the senior director of patience services and education from SHARE Cancer Support and the new Chair of the Metastatic Breast Cancer Alliance, speaks with Dr. Iyengar.
LINKS AND RESOURCES MENTIONED IN THE EPISODE:
FDA Approves Margetuximab-cmkb Plus Chemo in Pretreated Metastatic HER2+ Breast Cancer
AKT Inhibitor Disappoints in Tough-to-Treat Breast Cancer
SABCS 2020: Novel Oral Taxane Demonstrates Efficacy in CONTESSA Trial
Clinical Trials
NATALEE
OVERVIEW
00:01:40 - Introductions. (Jump to section)
00:06:04 - Early Stage Breast Cancer (BC). (Jump to section)
00:23:41- General Remarks about MBC. (Jump to section)
00:25:41 - Hormone Positive (ER+/PR+) MBC. (Jump to section)
00:31:40 - Triple Negative (TNBC) MBC. (Jump to section)
00:36:02 - HER2 Positive (HER2+) MBC. (Jump to section)
00:45:00 - Lifestyle Research (Jump to section)
00:47:28 - Question #1 about leptomeningeal disease. (Jump to section)
00:49:24 - Question #2 about oral SERDs. (Jump to section)
00:50:23 - Question #3 - should all MBC patients get genetic testing? (Jump to section)
00:52:21 - Question #4 about Lobular MBC. (Jump to section)
Christine Benjamin:
Welcome to the webinar “Report back from San Antonio Breast Cancer Symposium with a Spotlight on MBC.” I'm Christine Benjamin and the Senior Director of Patient Services and Education.
I'd like to introduce our speaker. Dr. Neil Iyengar is a board certified medical oncologist and physician scientist at Memorial Sloan Kettering Cancer Center, where he specializes in the care of patients with breast cancer. He also holds joint research appointments at the Rockefeller University Center for Clinical and Translational Science and Weill Cornell Medical College in New York.
Dr. Iyengar is a National Cancer Institute-funded principal investigator and an American Cancer Society research scholar. His research program focuses on the use of metabolic interventions, such as exercise, diet, and cardio-metabolic medications to reduce cancer risk and improve response to cancer therapy. He has been the lead author with multiple articles published in leading medical journals, and he has received grants and awards from several organizations, including the Breast Cancer Research Foundation, Conquer Cancer Foundatione, and the American Society of Clinical Oncology, among others. Dr. Iyengar, thank you so much for being here. We really appreciate it. And it's so good to see you again.
Dr. Neil Iyengar:
My pleasure and thank you. Good to see you and thank you for that lovely introduction. We were just chatting before everyone came online, and I mentioned that, I think, the last time I had the privilege of doing this was two years ago and that was in person. And so while I can't see any of your faces, and it feels a little odd speaking to my computer, I trust that everyone is there, and I look forward to having a discussion with you all.
I'm going to spend maybe about the first 40 minutes or so really highlighting what I think were some of the key advances that came out at San Antonio this year. And then open it up to questions about the research and about some of the recent therapeutic options that have been presented.
I'm going to really just talk because I think that's going to be more helpful in thinking about the broader treatment of breast cancer, then for me to show you specific data on slides. I'd like you all to take away from this, where the field is as a whole and where we're going.
So I hope you find that helpful. I've broadly outlined what I want to speak about into three categories. And this is a focus on MBC. So we'll be talking primarily about that category, but with the data that came out at San Antonio this year, you can't really talk about 2020 San Antonio without talking a little bit about some of the big studies that came out in the adjuvant setting or for primary breast cancer. When I say primary breast cancer, I'm referring to a non-metastatic breast cancer or stage 1 through 3 breast cancer, just to be very clear. So we'll spend a little bit of time on that, so I can highlight those major studies.
Then we'll move to metastatic breast cancer and I'll focus , of course, on the three classical phenotypes or types of breast cancer in general. And that is Hormone Receptor positive (HR+), HER2 positive (HER2+), and Triple Negative breast cancer (TNBC). And then, as you just heard, my own personal research interest is understanding how we can enhance or optimize our metabolic health, our metabolism to really improve treatment response to breast cancer therapies, whether that's in the prevention space, whether that's in the adjuvant space or whether that's in the metastatic space. We're learning a lot. And in fact, there was so much research in that area of improving metabolic health, whether through diet, exercise, or even medications like diabetes medications, that there was a whole session at San Antonio this year that was dedicated to that area. I had the pleasure of presenting the work of five other research groups that was presenting updated data at San Antonio this year. So I'll share some of that with you towards the end. So that's the general overview of what I hope to accomplish today.
And so let's get right to it. Let me also just put in a plug. I hope everybody is staying safe with all of the craziness of this year. Obviously, we've got some hope coming down the pipeline with regards to the pandemic.
Dr. Iyengar:
So let's get started with adjuvant therapy. The major advances that came out at San Antonio with regard to primary breast cancer have to do with the RxPONDER trial. And that's the use of a genomic test also known as the Oncotype score for women who have lymph node positive breast cancer. So that's one trial that I'll talk about.
And then the other area in the primary breast cancer setting that had some major data at San Antonio this year, were with regard to CDK4/6 inhibitors. And as those of you who are familiar with MBC, CDK4/6 inhibitors are molecular therapies used in combination with hormone therapy for the treatment of MBC. And there has been a lot of recent investigation, large clinical trials dedicated to understanding whether or not those drugs are useful for patients with primary BC. And as you'll hear me say, when we get into those trials, I actually think that some of the knowledge that we've gained in the primary BC space with regard to using CDK4/6 inhibitors, has actually informed our use of those drugs or will inform our use of those drugs for people with MBC. So it's a continuous landscape that we're talking about here.
Let's start with RxPONDER. That is the large clinical trial that used the Oncotype test to determine whether or not women with HR+ breast cancer stage 1-3 and positive lymph nodes will benefit from using chemotherapy or not. Let me give a little bit of background information on that.
As many of you may know or may not know, when a person has been diagnosed with a primary HR+ BC, the mainstay of curative therapy is to remove the cancer by surgery and also oftentimes radiation to clean up any remaining cancer. The problem is, what if microscopic cancer cells or circulating tumor DNA (ctDNA) had escaped the tumor from the breast before the surgery has happened, before the tumor has been removed.
That microscopic cancer can get into the lymph nodes. It can get into the bloodstream, it can get into any part of the body, and it can lay there undetected and dormant. It's too small to be seen on a scan. That is what eventually causes recurrence in metastatic disease.
And that is the rationale for giving systemic therapies like hormone therapies or chemotherapies before or after surgery in order to eradicate that circulating disease. Now, of course, it's not a hundred percent success rate. It is possible that circulating microscopic cancer can be resistant already or it becomes resistant to those systemic therapies. And so despite the use of systemic therapies, metastatic disease can still develop nonetheless. Clinical trials have shown us over the years that these systemic therapies are on average successful at preventing the continued growth of the micro metastatic disease.
So there's a lot of research being done right now on whether or not we can detect the presence of micro metastatic disease. You may have heard of circulating tumor DNA (ctDNA) . It is something that we're investigating for people with MBC. When you have breast cancer, whether it's a tumor in the breast that hasn't yet been removed, or if it's a breast cancer metastasis elsewhere in the body, that tumor is constantly shedding its DNA into the circulation. We have now learned that we can differentiate ctDNA from the normal DNA that's floating around in our system. And in the metastatic setting, measuring ctDNA may be helpful in understanding how the breast cancer is behaving. Is it getting ready to progress? Is it developing new mutations? It's still somewhat early days in terms of the use of ctDNA to measure a treatment response.
But a lot of work is being done in that field. Similarly, we're now trying to decide if we can use the approach of measuring ctDNA to help us risk stratify people with primary breast cancer. What is their risk of recurrence, or even to determine whether or not we should be escalating or deescalating treatments for people in the primary breast cancer space, based on their ctDNA profile.
Now, in that setting it's really early days. We don't know if it's helpful or not. And there is research going on in that area as well. And the reason, why I say it's really early days, is because you can imagine that if somebody has MBC and you can see it on the scan, there usually is some amount of detectable ctDNA. For somebody with primary BC, where you can't necessarily see whether or not they have tumor elsewhere in the body, you have to have a very good test to detect very tiny amounts of ctDNA. In other words, if I draw somebody's blood (this is also known as a liquid biopsy) and even if I draw two or three vials of blood, or even three or four or five or six vials of blood, and I look for ctDNA in those vials of blood [and don’t find any circulating tumor DNA], that's a minuscule fraction of the total blood volume in our body.
It cannot rule out the possibility of ctDNA in other parts of our body. And that's why that kind of testing or that kind of approach is not ready for prime time, certainly not in the primary BC space. We are getting there in the metastatic space, but not there just yet.
So what can we do in the meantime? In the meantime, we can look at traditional characteristics of the tumor, how big the tumor is, how many lymph nodes are involved to give us a sense of what is the risk that recurrence will happen. The estrogen receptor (ER) status is also helpful. The grade is also helpful. For people with HR+ BC, we have also found that looking at the expression of genes in the tumor can be helpful as well, because it tells us if the tumor is biologically programmed to metastasize. And that is what tests like the Oncotype score does.
The Oncotype is a genomic assay that looks at 21 genes. These genes are involved in tumor invasion and tumor metastasis, and it tells us if the tumor is genomically, programmed to travel. It also tells us if the tumor is susceptible to chemotherapy. And so for women with HR+ stage 1, lymph node negative BC, doing the Oncotype testing is basically a part of the standard of care.
We almost always do it unless the tumor is teeny tiny, less than half a centimeter If the Oncotype score is a high risk range, that tells us that the tumor knows how to metastasize, and we should escalate our therapy, and use chemotherapy followed by hormone therapy to try to lower the risk of metastasis. The big news about a year ago, actually two years ago now, was that we used to say that if you have a high risk score, you need chemotherapy. If you have a low risk score, you don't need chemotherapy. If you have an intermediate score, we don't know. And most of us would err on the side of caution, and we would use chemotherapy in that intermediate setting.
As many of you may have read in the news, the TAILORx trial was the last large trial that looked at intermediate risk scores for the Oncotype test and found that for post-menopausal women, if your score was lower than 25, which is getting into the intermediate risk range, you didn't benefit from chemotherapy.
So that dramatically changed our treatment approach. And now we can spare a lot of women with lymph node negative breast cancer from chemotherapy. On the other hand, if you were premenopausal and you had a score between 16 and 25, there was still a bit of a question mark, and we're still discussing using chemotherapy in premenopausal women, lymph node negative with a score of 16 to 25. So the RxPONDER trial builds upon that and says, ”Let's take it one step further. What if you have stage 1 through 3 breast cancer HR+, and it involves one to three lymph nodes?” That's the key distinction. If there's more than three lymph nodes involved, that person would not have been eligible for RxPONDER. They would have gotten chemotherapy in most cases. But what about these folks with one to three positive nodes and HR+/HER2- BC? So what the RxPONDER trial did, it checked the Oncotype score. If your score was 25 or below you were randomized to chemotherapy or no chemotherapy. And essentially there was some fancy statistical designing. So if you actually look at the trial and read the study results, you're going to see terms like interactions and whether the predictive hypothesis was met or not met, would determine whether or not the prognostic hypothesis should be examined.
I'm just going to distill all of that to tell you the bottom line was that for post-menopausal women with hormone receptor positive breast cancer, stages 1-3 with one to three positive lymph nodes, if the Oncotype score was 25 or below, there did not appear to be a benefit of chemotherapy.
And so that is very much practice changing because we generally err on the side of offering chemotherapy, if a lymph node is involved. What this is telling us is that, that doesn't appear to be helpful. And so now the practice is changing, we're not necessarily recommending chemotherapy for that group.
One of my patients asked me very astutely. “If the cancer traveled to the lymph node, doesn't it mean it knows how to travel?” That is possible. But it's also possible that the cancer cells simply drained to those lymph nodes from the breast and traveled there through the drainage stream.
The Oncotype score is a genomic test. So it helps us make that distinction --was the cancer genomically programmed to travel or did it just get there? And these results would suggest that if the score is lower than 25, even if it got to the lymph nodes, it's not going to get much further. If it is going to get much further, if it is going to continue to travel, chemotherapy is not going to stop it, but hormone therapy will. So that's the key finding for post-menopausal women. For premenopausal women it gets a lot murkier, and in the premenopausal setting if there are one to three positive lymph nodes, it looks like chemotherapy may still provide a small benefit. And so for premenopausal women, the practice is not really changing, at least not yet where we're not willing to say, “Ok, you don't need chemotherapy because based on RxPONDER trial, we cannot rule out a benefit.”
In fact, there appears to be a benefit of chemotherapy for premenopausal women with one to three positive nodes. So that was the RxPONDER trial. That was the big news in the primary breast cancer setting.
The other trials in the primary breast cancer setting that I need to mention are with regard to CDK4/6 inhibitors. And so many of you are familiar with the three CDK4/6 inhibitors that are approved for the treatment of HR+ MBC. That's Ibrance (palbociclib). That was the first CDK4/6 inhibitor to be approved. And then Kisqali (ribociclib) and Verzenio (abemaciclib). And many of us have felt for a long time that these three drugs are very similar, if not the same. In the trials, testing these drugs in the metastatic setting -- the PALOMA and the MONALEESA trials -- these trials essentially all showed very similar results that these drugs were very effective. We are all very excited about the CDK4/6 inhibitors for prolonging PFS and OS when combined with hormone therapy and the magnitude of benefit seemed to be very similar amongst the three drugs.
They are each a little different in terms of side effects. We know, for example, Verzenio(abemacyclib) doesn't suppress the blood counts as much as Kisqali(ribociclib) and Ibrance(palbociclib), but on the flip side abemacyclib tends to cause more GI side effects like diarrhea than palbociclib or ribociclib.
Kisqali(ribociclib) is the only one of the CDK4/6 inhibitors that has a clinical trial specifically dedicated to premenopausal women, that's the MONALEESA-7 trial. The other two CDK4/6 inhibitors did have premenopausal women enrolled on some of their trials, but those were trials mostly included post-menopausal women.
So if you're a data purist, you would say that ribociclib has the most data for premenopausal women, it has been shown to have an overall survival benefit. In other words, it prolongs the life of pre-menopausal and post-menopausal women with metastatic HR+ breast cancer.
And so for many of us, including myself, ribociclib is my CDK4/6 inhibitor of choice for premenopausal women. For post-menopausal women they all seem to be similarly effective. However, we're now learning that there are some differences when we start thinking about bringing these drugs in earlier.
So the question has been lingering for some time about whether or not, since these drugs are so effective for people with metastatic breast cancer, should we be offering these drugs earlier to try to reduce the risk of developing metastatic breast cancer? And so all three CDK4/6 inhibitors have launched trials testing the combination of hormone therapy, which you would normally give in the adjuvant setting for primary breast cancer, but now adding a CDK4/6 inhibitor, and at San Antonio this year two of those trials were reported. And just to provide a little more background, one of the largest trials, the PALLAS trial, was reported before San Antonio. It was a combination of palbociclib with hormone therapy as part of adjuvant therapy for patients with primary HR+ breast cancer.
And it was a big trial. We participated in the trial, and unfortunately it was a negative trial. There did not appear to be a benefit of adding palbociclib to hormone therapy to reduce the risk of metastasis for women with early stage HR+ breast cancer. Now the problem with that trial was that there was a high rate of discontinuation. A lot of people stopped the palbociclib either because of side effects or because it was suppressing the blood counts. And so we thought that, perhaps, it was the discontinuation rate that was contributing to that lack of efficacy for adding palbociclib. So we all awaited the PENELOPE trial, which was reported at San Antonio. The PENELOPE trial focused specifically on people with non-metastatic breast cancer, but higher risk breast cancer that was more likely to become metastatic, either because the lymph nodes were positive or other biological features that made the breast cancer higher risk. Unfortunately, the PENELOPE trial was also negative. We did not see a benefit of adding palbociclib for hormone therapy for reducing the risk of metastasis.
[00:19:46]And so that's two negative trials in the adjuvant setting for palbociclib. However the story's a little bit different for abemaciclib. Abemaciclib is another CDK4/6 inhibitor and that drug was combined with hormone therapy, again for people with primary breast cancer. And there was indeed a benefit.
There was a reduction in the risk of recurrence, a significant reduction in the risk of developing metastatic disease when abemaciclib was added to hormone therapy. And we saw that reported in the MONARCH-II trial at San Antonio. And so while we are awaiting approval, several of us are starting to offer abemaciclib in combination with hormone therapy to our patients with the highest risk non-metastatic breast cancer based on these data, there is one more trial that we're waiting for the data to be reported. And that's the NATALEE trial that is testing whether the combination of ribociclib with hormone therapy is effective. And I'm anticipating that data will be reported soon if not at ASCO, then at next year’s San Antonio.
So far we see conflicting results. We see negative data in the adjuvant setting for palbociclib. We see positive data for abemaciclib, and we're awaiting the data for ribociclib.
What does that mean for the metastatic setting? Nothing, to be technically accurate. But it does start to make us question. Are these drugs a little bit different? Maybe in the metastatic setting it doesn't matter. And as we've seen in the trials, all three of these drugs are efficacious. But perhaps, there are some subtle differences between the drugs that do matter in the primary or non-metastatic setting.
The other difference that I'll add is, we know that abemaciclib has some CNS activity. It can be helpful for people who have breast cancer that has traveled to the brain. And so when I'm thinking about which CDK 4/6 inhibitor to use in the metastatic setting, that's one of the first things that I think about. Does this person have a involvement of the brain or the spine or the cerebral spinal fluid?
And if so, I would gravitate towards abemaciclib for that person. So those are the big trials. Of course, there was a lot presented, but that's the big news for the non-metastatic setting.
Dr. Iyengar:
And we'll move on now to the metastatic setting. The first thing I'll say about the metastatic setting is it's not going to be possible for me to do justice in the time that we have to all of the research that's been done. But we saw a lot of phenomenal research both on the scientific side, in terms of understanding the biology of breast cancer in the metastatic space.
I talked a little bit about that, when I started going on the tangent about ctDNA. But that's a taste of what's going on in terms of the science. People are looking at whether or not we can profile the mutations and the biology of breast cancer by looking at ctDNA, so that we don't necessarily have to go do a biopsy every time. We want to re-characterize the breast cancer in the metastatic setting. Again, that research is ongoing. We're learning more about the tumor microenvironment and the immune cells that surround the breast cancer tumor, both the primary tumor in the breast, but also at metastatic sites.
We're learning about reprogramming of metastatic disease. If there are more than one metastatic site, it turns out that the tumor DNA may be able to communicate with each other by traveling in little pods called exosomes in the bloodstream. And so what that means for treatment, if one tumor site, one metastatic site develops a resistance mutation, and is able to start growing, how does that confer that information to another metastatic site?
It might be through these exosomes. A lot of that is very preliminary right now, but very interesting, nonetheless, because that is going to have direct implications down the road on how we approach the treatment of metastatic breast cancer and whether or not we can change the trajectory of the cancer by really understanding biology and how the communication between metastatic sites occurs, how the micro environment plays a role in either inhibiting or fostering the growth invasion and metastasis of the cancer cells. There was a lot of biology presented at San Antonio this year.
Dr. Iyengar:
So our knowledge is advancing. There are a couple of big trials that I think are important to discuss here when we talk about metastatic space. We first start off with ER+ breast cancer, there's a lot of work that's being don in ER+ breast cancer with new molecular therapies coming down the pipelines.
There are new types of CDK4/6 inhibitors being studied. There are CDK2/4/6 inhibitors in Phase 1 and Phase 2 trials that are being tested. There are new types of antibody drug conjugates (ADC) that are being tested. And there are new chemotherapies that are being tested as well.
And one of the big trials was the CONTESSA trial. This was a Phase 3 trial of Tesetaxel, which is an oral version of Taxol. Many of you are familiar with that drug. And obviously, especially in the current era, where we're trying to minimize people's exposure to one another and to the outside, an oral therapy is very attractive, so we don't necessarily have to bring in people for infusions.
And so CONTESSA was a large Phase 3 multicenter trial that looked at the combination of this oral version of Taxol, Tesetaxel, plus Capesitabine(trade name Xeloda), which is another oral chemotherapy that I'm sure many of you are familiar with, versus Capesitabine alone for people with HR+ MBC. And I should also clarify that in this particular trial, it was specifically for people who had previously gotten Taxol. And so that's important and I'll explain why in a minute, but essentially there was a benefit. There was a benefit in preventing the progression of metastatic disease with the addition of Tesetaxel to Capesitabine. And so we anticipate that, based on the results of this trial, many of us are predicting that the FDA will likely approve Tesetaxel as a new treatment option for metastatic breast cancer in combination . Now, the reason why it's important that this trial included patients who had previously gotten a taxane.
It tells us that Tesetaxel is effective, even if a person's gotten Taxol before. We often think that if you've been exposed to one type of treatment and the disease progresses it may not be a good idea to reuse that treatment and by extension, it may not be a good idea to use a drug that's related or within the same family of that treatment, because the cancer may have developed resistance to either that specific treatment or that family of treatments. And certainly that was the thinking for Taxol. If somebody had progressed on Taxol, then we were unlikely to use another taxane to treat a person.
This shows us that Tesetaxel, which is a taxane, but an oral version, does seem to be effective despite progression after exposure to Taxol. And so that's important because now we know we don't necessarily need to eliminate this treatment option if somebody's gotten Taxol in the past.
So I think, that's important because this transition after somebody has gotten hormone therapy, molecular therapy and so forth, moving on to chemotherapy can be a challenge. You're now moving on to a treatment that has more side effects as IV infusion and so forth. But now with the option of Tesetaxel, we have another oral chemotherapy available to us.
It's well tolerated, and we certainly are pleased to see another treatment option that will likely become available soon to us for metastatic HR+ breast cancer.
There is earlier phase work going on Phase 1 and Phase 2 trials. As I mentioned before, in terms of other treatment options, molecular therapies, there was one Phase 3 trial IPATunity130 of a molecular therapy called an AKT inhibitor.
Unfortunately, that was a negative trial. But that may be a problem or a characteristic of that specific type of AKT inhibitor. There are other AKT inhibitors that are in development right now. And so we're looking forward to data from those types of molecular therapies. And just to give you some context there is a PI3-kinase inhibitor called alpelisib, which is a molecular therapy that is already FDA approved.
Most of us are using it in the second line space, meaning in the first line treatment, somebody getting hormone therapy plus CDK4/6 inhibitor. And then if a person has a PI3-kinase mutation in the tumor in the second line space, most of us are using this FDA approved drug alpelisib in combination with hormone therapy like Fulvestrant.
But of course, the search is on for more molecular therapies before we have to turn to chemotherapy. So I would say, now we have a new oral chemotherapy option.
Keep your eyes open for a new class of drugs called antibody-drug conjugates (ADC). There is a drug called sacituzumab govitecan (Trodelvy), which you may be familiar with.
That is an antibody-drug conjugate. It is a protein and antibody that has been fused with a chemotherapy. And I think of it as a homing missile, the protein directs the chemotherapy specifically to the cancer cell. And the idea is that it makes it more potent. So the chemotherapy finds the way directly to the cancer cell.
And it helps to spare the normal cells, the healthy cells, so that you experienced less side effects. Sacituzumab is one of those antibody-drug conjugates, which has recently been approved for the treatment of metastatic TNBC And it is now being tested for ER+ breast cancer.
There is a large Phase 3 trial TROPICS-02 that is going on right now. We're participating in it here at Memorial and it is testing sacituzumab for ER+ metastatic breast cancer after somebody has received hormone therapy. So I think, lots to be hopeful for in this space. There are a lot of new molecular therapies coming down the pipeline. And then this new class of drugs, the antibody-drug conjugates are also coming down the pipeline.
Dr. Iyengar:
Let me shift over in the interest of time to triple negative breast cancer (TNBC) . And there again, a lot of very exciting things coming out of San Antonio with regard to better understanding of the biology of triple negative breast cancer.
New types of therapies are being studied. I'm sure you all have heard about immunotherapies that are showing to be very promising in TNBC. We have an FDA approved immunotherapy tocilizumab for the treatment of triple negative breast cancer. That’s for patients who have PD-1 or PD-L1 positive TNBC. That is a type of protein or molecule found in the micro environment. And it's important to be specific about that because it's not necessarily found on the tumor itself. What we're learning is that the immune cells in the micro environment, like the T-cells and other white cells in the microenvironment, are important for how the tumor responds to cancer therapy. A lot of these immunotherapies are helping to rev up the T-cells and other immune cells in the microenvironment so that they can work in conjunction with the chemotherapy to be more effective at killing the cancer cells.
And so tocilizumab is currently in use typically in the first-line setting as the first treatment in combination with Abraxane, which is a type of taxane for triple negative breast cancer. So what came out at San Antonio, of course, was the keynote studies. One of the keynote trials is pembrolizumab, which is another type of anti PD-1/PD-L1 therapy for breast cancers and other cancers, and we see positive data. So the combination of pembrolizumab with chemotherapy is effective for the treatment of metastatic triple negative breast cancer. And what's interesting, we're learning that the effectiveness may go beyond the classical --are you positive for PD-L1 or PD-1 or not? There are other markers that we're looking at, immune markers that may predict benefit from the addition of immunotherapy to chemotherapy. We're also seeing that may be effective, not just for metastatic TNBC, but in the pre-surgical space, in the neoadjuvant space.
We've seen data recently prior to San Antonio that the addition of pembrolizumab to chemotherapy in the pre-surgical space increases the rates of pathologic complete response or shrinks the tumor more. When you add on that immunotherapy and think that what we're seeing now is where we're going to have more immunotherapy options for triple negative breast cancer.
And it's also giving us the data that we need to start testing these immunotherapy options for other types of cancers -- for HER2+ cancers and maybe for some people with HR+ breast cancers that show a specific immune signature. There is some thought that combining immunotherapies with PARP inhibitors for people with BRCA mutations may be helpful.
It may actually potentiate or increase the efficacy of the immune therapy. So that's being studied as well. Some of those data were presented in poster format at San Antonio, but again, that's all very early phase right now. We're awaiting the larger trials to be completed. But I just want to give you the sense that all of that research is going on right now, it is looking promising.
So I think that we will see a lot coming from the immunotherapy field. But currently we have FDA approved tocilizumab, and now we have pembrolizumab showing positive data in a large Phase 3 trial, which is very encouraging for the treatment of triple negative breast cancer.
There's a lot of work going on with regard to PARP inhibitors, both for people who have germline BRCA mutations, but also it is being tested for people who don't have a germline BRCA mutation, a mutation that you inherited or that you can pass down. That's the traditional genetic testing, but we can also look at the genes within the tumor itself. So it's possible for somebody to have a BRCA mutation in the tumor, but not in the genes that you inherited or passed down. And so we're now testing whether or not PARP inhibitors are effective for those folks, who have a mutation, that's called a somatic BRCA mutation in the tumor but not in the inheritable genes.
So that I would say stay tuned for, I think that's an exciting area of research as well.
Dr. Iyengar:
And then that brings me to HER2+ metastatic breast cancer. Again, a lot going on in that space. And I think to do that area justice, I would have to zoom out, not just from San Antonio, but from what's really been going on in the last year, because this has been a very active year for HER2+ MBC.
We now have three new therapies that have been recently approved for the treatment of HER2+ metastatic breast cancer.
Of course, there's neratinib which is an oral treatment. It's not a chemotherapy. It is a molecular therapy. It's a tyrosine kinase inhibitor.
Neratinib in combination with capesitabine oral chemotherapy has been shown to be effective at prolonging time to disease progression or tumor growth for HER2+ metastatic breast cancer. It may even be helpful for people who have brain metastases.
Neratinib is a little bit of a challenging drug. It causes a lot of diarrhea. It has been approved by the FDA for extended use in the adjuvant setting. So after someone has completed Herceptin you can take neratinib for a year, even two years to try to reduce the risk of metastasis.
The problem though is the benefit in that setting is fairly small. Very small, I should say. It's roughly less than 2% in terms of preventing or reducing the risk of developing metastatic disease. And it's a lot of diarrhea. And I'll tell you it's been a challenge. And I think that most people reasonably decide not to do it in that setting.
However, in the metastatic setting, it is now an additional treatment option and that has been approved by the FDA in combination with capecitabine. Our strategy in the metastatic setting is to really develop as many therapies as possible and get as much mileage out of them as well to really prolong survival.
And so the more treatment options we have, the better and so neratinib plus capecitabine would be a treatment option for metastatic HER2+ breast cancer. And it may be beneficial at also treating brain metastases. It’s still difficult in terms of the side effect profile with the diarrhea, but certainly manageable.
Then we've had the approval of an antibody-drug conjugate. So going back to that concept of molecularly fusing chemotherapy with a protein or antibody that targets the chemotherapy to the cancer cell. And the Daiichi compound, which is the drug of Daiichi, the drug is known as Enhertu, it was approved in the last few months by the FDA for the treatment of HER2+ metastatic breast cancer.
hat is an antibody-drug conjugate. And that has been significantly effective in prolonging progression-free survival. It is a fairly well tolerated antibody-drug conjugate again, because it's serving as a homing missile for the chemotherapy, it's reducing some of the toxicities or the side effects to our normal cells.
So that's been, in my opinion, a very effective new therapy that's been approved this year for the treatment of HER2+ MBC. The thing to keep in mind about that therapy is the major risk from that therapy. It can cause an inflammation of the lungs and roughly 15% of people who are treated with it. And that's called a pneumonitis. And many oncologists are checking pulmonary function, testing or watching your lungs closely. Certainly, if you develop a cough and you're being treated with Enhertu, you should let your oncologist know right away to make sure that side effect is not developing.
The third treatment option that was recently approved by the FDA is Tukatinib or Tukysa is the brand name. And that's a drug by Seattle Genetics. Tukatinib is also a tyrosine kinase inhibitor just like neratinib, but it's a lot more specific. Neratinib is considered to be a panher tyrosine kinase inhibitor.
So as you may know, there are different HER molecules, not just HER2, there's HER1, HER2, or HER3 or HER4 and so on. Neratinib kind of hits all of them. Tukatinib hits specifically HER2. We think that's beneficial because it's very well tolerated.
It's got a lot fewer side effects. There is potential for diarrhea, but it's a lot less, there's less skin toxicity and so forth because it's really targeting specifically HER2. So to Tukatinib in combination with Capecitabine and Herceptin has been approved for the treatment of metastatic HER2+ breast cancer and significantly prolonged progression-free survival. And interestingly has been shown to be very effective for brain metastases. In fact, it prolongs progression free survival in the brain as well. In other words, it helps to reduce the risk of existing brain metastases from growing, and it might even reduce the risk of developing brain metastases in the first place.
So that's a very exciting new treatment option. And there will be a lot of continuing research that is being done on all of those new treatment options. As we learn more and get more experience with those treatments.
There are a lot of other drugs that are currently in the pipeline that are not ready for prime time yet.
There are some of the ones that are probably picking a lot of people's interests are new antibody-drug conjugates, new tyrosine-kinase inhibitors, like Tukatinib, are coming down the pipeline. There are new types of antibodies, bispecific antibodies. These are antibodies that target not just HER2, but maybe HER2 and HER3 or others.
And it's essentially a dual inhibition approach. So there are bispecific antibodies that are currently in development. Probably the bispecific antibody that's the furthest in development is by Zanidatamab by a company called Zymeworks. And so they continue to present updated data at these conferences as well So stay tuned for more data in terms of the efficacy of bispecific antibodies. .
Margetuximab, for example, is another type of antibody. It's not a bispecific antibody, it's a new type of antibody that may be helpful with data that has been presented by Dr. Hope Rugo and others at ASCO and at San Antonio.
And I have to tell you that I wasn't really impressed by the magnitude of benefit. That was shown with Margetuximab. It was fairly small and especially part of the reason why I wanted to outline to you all of the other treatments that have been recently approved for the treatment of HER2+ breast cancer.
I think that now we've got several other treatment options with dramatically better results. Of course, you never want to compare drugs unless they've directly been compared in a clinical trial, but I think we also have to be practical. And when you look at the magnitude of benefit for some of these recently approved drugs for HER2+ MBC you see pretty dramatic benefit from drugs like Tukatinib and Enhertu.
I wasn't terribly impressed by what we saw with Margetuximab. However, there was a benefit, so we can't minimize that. And also I think it's an evolving space because there's also data to suggest that the response to Margetuximab may depend on the biology of the tumor. There is some heterogeneity in how HER2 is expressed, the way that HER2 is expressed for some people's breast cancer is different than how it is expressed for other people with HER2+ MBC. And that has to do with the types of genes that are turned on or turned off in the tumor. And that can impact the affinity or the stickiness of how well the anti-HER2 antibody binds to the HER2 receptor.
If you have a HER2 receptor that's not very sticky, then the antibody is just going to fall off and it may not be effective. But if you have a HER2 receptor that's very sticky (I apologize for being so reductionist about it, but it helps me to think about these drugs), then the antibody will bind and adhere and may be more efficacious. And so we're starting to learn that's playing a role in how people respond to Margetuximab. On top of it I talked earlier about the immune microenvironment for TNBC. That's also important for HER2+ breast cancer.
And so for HER2+ breast cancer, the T-cells that are present and other immune cell infiltrates in the tumor microenvironment may also play a role in how a person responds or how a tumor responds, I should say, to Margetuximab. So I have not closed the door on that treatment option, there is a benefit, it's small and perhaps the benefit may be greater.
It might even be profound when we identify the right immune signature and the right affinity signature, the stickiness signature. And if we can identify the people with those kinds of signatures that predispose them to respond well to Margetuximab, then this might turn out to be a really good treatment option for those people.
So there's a lot of research that's being done to try to elucidate that.
Dr. Iyengar:
We're getting close to time and I've already exceeded my own outline restrictions. So apologies for that. I do want to leave time for questions and answers. I'm just going to say really quickly about lifestyle research.
There was a lot that was presented, you might've seen a big trial was presented, a French trial which showed that a low-glycemic diet, in other words diet that is used to prevent or treat diabetes was helpful for reducing the risk of developing breast cancer in the first place.
But also for people who are diagnosed with breast cancer, there was another large trial (DEDiCa) that showed that in women, who adhered to the diabetes prevention program diet, they had prolonged survival. They lived longer after a breast cancer diagnosis. And so take a look. The diabetes prevention program is widely available. You can Google it and see what that diet consists of. Many local community centers like the YMCA offer courses on how to implement the diabetes prevention program in your own life. The Live Strong program is a version of the diabetes prevention program that is also available at many centers locally.
So you can find these resources online and you can certainly engage in those programs.
There are a lot of studies, we at Memorial are currently testing exercise in combination with CDK4/6 inhibitors and hormone therapy for people with metastatic disease. That trial is ongoing right now, we're testing different diets.
We have a trial of a plant-based diet. We have a trial of a ketogenic diet that's coming up. Right now I'm not endorsing any of those diets. There's a lot of information out there that's being talked about, but most of that is not based on randomized prospective trials. And all of the drug data that I just outlined to you is randomized prospective trials.
And in my own opinion, we should be applying the same vigor of research to diet and exercise trials, which is what we're doing. We just don't have that data yet. And that's why I am agnostic. In other words, I'm unbiased. I don't particularly recommend a diet in the metastatic setting until we have the data we're testing, like I said, keto, we're testing plant-based we'll see, hopefully we'll have recommendations soon.
I think it will depend on the biology and the genomics of the tumor. But in general, I do recommend a metabolically healthy diet, which is either a diabetes prevention diet, or a diet that's high in fiber and fruits and vegetables. So I will end there and there was a lot to talk about, but I hope there was some semblance of organization there.
I hope you found this helpful. And let's go ahead and open it up to questions. Thank you.
Christine Benjamin:
Thank you, Dr. Iyengar, you presented a lot of information, all very good information. And you presented it in a way that was easy to understand. So thank you so much for that. We do have a few questions. So as you mentioned, there've been a couple of drugs recently that seemed to be effective for brain mets. Is there any research underway for treating or, hopefully, maybe even ideally preventing, leptomeningeal disease?
Dr. Iyengar:
That's a great question. So for those of you that don't know, leptomeningeal disease is when the cancer has gotten into the lining of the brain and the spinal cord. And that can be tricky to treat because you're not treating directly at tumor, but you're detecting like a spread out cancer amongst the lining. And so radiation, for example, can be challenging to use because you'd have to radiate a lot of area, which can, of course, cause side effects.
Unfortunately, a lot of these drugs that I just outlined, while they included people with brain metastases, they excluded people with leptomeningeal disease. So I can't comment on the efficacy of these drugs for people with leptomeningeal disease. However, with that being said, there are reasons to believe that theoretically these recent approvals should be effective for leptomeningeal disease as well.
I think time will tell, as we gain more experience using these new therapies. Certainly, if I have somebody who has leptomeningeal disease and we've gone down the standard treatment options, then this would be something like Tukatinib, for example, is something that I would consider trying.
Now it's certainly not based on data, it's off-label, but it's something I would think about. There are earlier phase trials that are looking at treatments for leptomeningeal disease. Many of them are combination treatments with radiation, for example. And so there's a lot of earlier phase work that's going on in the setting.
So hopefully we'll have something more tangible to offer in the near future.
Christine Benjamin:
Thank you. And then someone was asking if there's any news on the EMERALD trial with Fulvestrant versus the oral version of Fulvestrant?
Dr. Iyengar:
That's a great question. So there is no news yet. But that is something that we're watching closely.
There are a couple of oral Selective Estrogen Receptor Degraders (SERDs) like Fulvestrant (well, Fulvestrant is not oral, but it is a SERD), but there are a couple oral versions of it that are in development right now that are being tested. One of the promising things about that class of oral SERDs, just like Tesetaxel, the oral taxane, is that it's now starting to become, I don't want to say clear, but the possibility has surfaced that these oral SERDs may be effective even after somebody has gotten Fulvestrant.
and if that's the case, that would be great because that would add another treatment option to our toolbox for metastatic breast cancer. No big news yet on that trial, but it’s promising.
Christine Benjamin:
So our friend Shirley [Mertz] is asking, “Should all MBC patients undergo genetic testing?” The topic was debated at SABCS by two oncologists. Why are we still asking this question?
Dr. Iyengar:
Thanks, Shirley. That's a great question. And I'm sure as you probably know, I'm biased because the oncologist who debated for it, is somebody I work with. And I think it's challenging. In full disclosure I do it. I test. All of my patients certainly with metastatic breast cancer for it, so it's hard for me to actually argue why we shouldn't do it. But the reason why people don't do it, is because let's say I have somebody who has metastatic breast cancer, and we do genetic testing, and she has ER+ MBC and a BRCA mutation. The question then becomes. Do you use a PARP inhibitor? Where do you sequence it, when we've got all of these other great therapies for ER+ breast cancer, do you use it in combination with these treatments? I actually just had a patient this morning who we had this very conversation with. We did the genetic testing and we found she has a BRCA mutation, just ER+. We're using molecular therapies, hormone therapies. So I think that people that are not excited about doing it, are waiting for data.
There are trials that are testing combinations and sequencing and all of that to show that there is clinical action that can be taken. When you have the benefit of being at a research center like this, we can take actions.
We have trials. We have the benefit of knowledge from those trials, the ongoing science where I personally feel that genetic information is useful. But certainly for somebody who maybe lives in an area that is not served by an active academic center and can only use on label approved therapies, then getting that information may not help to direct that kind of treatment approach. But I'm biased and I think it can be helped.
Christine Benjamin:
So we're just about out of time. I'm going to squeeze in one more question. Any specific lobular research in other treatment or imaging.
Dr. Iyengar:
Yeah, that's a great question. So there's a lot of biology research that's being done. There's nothing that I can think of off the top of my head that was major at San Antonio, but study is being done with regards to imaging using specific biologic tracers, like tracers that target the estrogen receptor, for example, to try to see if we can improve the sensitivity of picking up lobular disease on radiographic as I'm sure, picking up lobular disease on radiology tests is challenging both because of the way that lobular grows and the pattern in which it grows.
And so there is work being done in improving radiographic techniques by adding these kinds of biologic tracers. And I should also add that. I think for those of you that are involved in the patient side of research with regards to helping us understand patterns of lobular carcinoma, that's really important.
I hope people here know about MBC Connect which is an app… Shirley [Mertz] is here. She could tell you all about it better than I could. But I've had the privilege of being involved in looking at this from a scientific and data standpoint.
We think there's a lot that the scientific community can learn from people who are diagnosed with metastatic breast cancer. And so this is a digital app or platform that allows you to put in your information. But it also helps people in terms of connecting them with one another, but also helping you with clinical trial matching and identifying other resources that may be available to you.
There is integration with other research initiatives, questionnaires and understanding lobular carcinoma better, for example. So I would certainly say check out MBC Connect, if you haven't already.
Christine Benjamin:
Thank you so much, Dr. Iyengar. You have been terrific as usual. We so appreciate your time and your expertise and again, everyone, thank you so much for joining, please visit our website ww.sharecancersupport.org, and also MBCconnect@thembcalliance.org website. Thank you so much. Thanks everyone. Have a great holiday season.
