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Breast Cancer Research at ESMO 2020
Michael Method, M.D.
October 12, 2020

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Dr. Michael Method is an oncologist and also senior medical adviser and global lead for adjuvant breast cancer treatment research at Lilly Oncology.

While ESMO 2020 was virtual this year, there was still quite a bit of breast cancer research presented. Dr. Method joined us to talk about some of the most notable studies.

Listen to the podcast to hear him discuss:

  • studies looking at using the CDK4/6 inhibitors Verzenio (chemical name: abemaciclib) and Ibrance (chemical name: palbociclib) to treat early-stage hormone-receptor-positive, HER2-negative breast cancer
  • a study using the immunotherapy Tecentriq (chemical name: atezolizumab) to treat early-stage triple-negative breast cancer before surgery

Running time: 27:16

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This podcast has been made possible by the generous support of Lilly Oncology.

Welcome to the Breastcancer.org Podcast, the award-winning podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org senior editor, Jamie DePolo.

Jamie DePolo: Hello, and thanks for listening. Dr. Michael Method is an oncologist and also senior medical advisor and global lead for adjuvant breast cancer treatment research at Lilly Oncology. There were several studies on breast cancer presented at the European Society for Medical Oncology Virtual Congress 2020. Dr. Method joins us to give a summary of some of the most important research.

Dr. Method, welcome to the podcast.

Dr. Michael Method: Thank you. I'm happy to be here.

Jamie DePolo: Great. So, ESMO 2020 was virtual this year because of the pandemic, but there was still quite a bit of breast cancer research presented. So could you talk a little bit about the research that really stood out for you, and then tell us what you think that research means for patients?

Dr. Michael Method: Absolutely, and again, thank you for the opportunity to be here today talking with you.

I think the first thing that really popped out in the breast cancer space really has to be the monarchE trial. And I know perhaps many have heard already about the details of the trial, but this trial really has the opportunity to change the face of the treatment and management of patients with early breast cancer.

The trial was actually designed specifically for the hormone-receptor-positive, HER2-negative, node-positive breast cancer patient population that have higher risk of recurrence. And in that patient population, we actually were able to demonstrate a 25.3% improvement in this concept we call invasive disease-free survival — basically, the cancer coming back.

And that really was an absolute benefit of 3.5% at the 2-year mark when this analysis was done. And this reached a very significant P-value, suggesting that this trial was a definitive improvement in the treatment and management of patients in this population.

Particularly important in that trial was really the risk of distant recurrence prevention by a large 28.3%. And again, we have to clearly understand that the benefit was achieved within that 2-year period of time of treatment, which is the first time in the last 15 to almost 20 years where there's been that significant of an improvement in the treatment and management of this patient population.

Fortunately, the safety and tolerability of this trial met all of the criteria and safety criteria that was anticipated, and there really are no new findings with regards to safety, side effects, toxicities, or adverse events.

Moving on to a less favorable trial, but one that was quite important, and one that involved a number of patients throughout, was the PALLAS trial. The PALLAS trial actually looked at a similar population to the monarchE trial, and in that trial, this again, randomized, phase III, open-labeled trial, actually looked at all stage II-III early breast cancer, which was a less high-risk group than the monarchE trial looked at.

And this trial, just prior to the ASCO meeting, declared a futility analysis, basically saying that the trial was not efficacious and did not improve the outcome of patients. Why this is so important is because the two trials, put side by side, really identifies and emphasizes the importance around the identification of those patients at the highest risk for recurrence who need more therapy.

Again, they need their therapy escalated, as opposed to by the current standard, which is a combination of surgery, radiation, and/or chemotherapy plus endocrine therapy. The use of the molecules that were studied in this group are what we call the CDK4/6 inhibitors, and this class of drugs, which is now commonly used in the metastatic breast cancer setting, has now been moved to the early breast cancer setting, with abemaciclib, or Verzenio, now demonstrating efficacy in that highest risk patient population for recurrence.

Just to say it again, this is the first time in the last 15 years that an improvement in that patient population has been identified and, indeed, an identification of those patients for which escalation of therapy is necessary has occurred.

Jamie DePolo: I'm sorry to interrupt. I just want to ask, just so we’re clear. I know the monarchE trial was looking at using Verzenio in addition to hormonal therapy. And I'm sorry, the PALLAS trial, was that looking at a different CDK4/6 inhibitor?

Dr. Michael Method: It was. That trial was looking at Ibrance, or palbociclib, and that’s one of the three CDK4/6 [inhibitor]s that are approved and have shown benefit in the metastatic setting.

Many reasons why that trial may have failed. A couple include the choice of a less high-risk population; so those that do just as well on endocrine therapy alone. And the second is like the tolerance of the drug: 42% of the patients in the PALLAS trial, with the use of Ibrance, had to discontinue the drug prior to finishing the therapeutic treatment. Whereas abemaciclib, that number was 16%, and so the fact that the abemaciclib was a more tolerable treatment and treated a high-risk patient population likely was the reason why abemaciclib, with the trade name of Verzenio, achieved significance and improvement in that patient population.

And the point here, really from an emphasis perspective is, there are patients, in the early breast cancer space, that actually need better treatment. And the monarchE trial has identified that patient population that not only does worse without additional therapy, but also who will benefit from abemaciclib, or from Verzenio, in that patient population.

So, really important information, and again, literally something that hasn’t happened in that patient population for the past 15 to 20 years.

Jamie DePolo: Great. What else sort of caught your eye in the research?

Dr. Michael Method: Well, moving right on to metastatic breast cancer. I think that the next, really most important presentation and data that was released at ESMO was the late-breaking abstract #18. This was the final overall survival analysis from the trial we call the SOLAR-1 trial.

In this trial, we actually were looking at specific PIK3CA-mutated breast cancers, which are present at 40–45% of the breast cancers that actually exist today, and this is a drug that has previously been FDA approved, and approved both in the United States and in Europe, for its improvement in progression-free survival, meaning that it delayed the onset of recurrence in the metastatic space already. This was a follow-on for the overall survival benefit in that patient population.

This drug is called alpelisib, and is a specific biomarker-driven treatment that specifically treats patients that have this specific genomic mutation, called a PIK3CA mutation. And again, the benefit of this drug has been demonstrated in the progression-free survival side, which was presented previous to this, and demonstrated an 11-month improvement of disease-free interval as opposed to 5.7 months in patients with this particular mutation.

Unfortunately, the overall survival did not reach statistical significance. However, there was a trend towards an improvement in overall survival, and there were patients that had the worst kind of disease, such as lung or liver, that did demonstrate an improvement in overall survival.

This trial did not include patients that had received a prior CDK4/6 inhibitor, which is the type of drug we just spoke about that has been moved up into the early setting. And despite its toxicity, we still believe that alpelisib, or these directed PIK3CA mutation-type drugs, are going to have a role in the treatment of metastatic breast cancer, but likely after the use of the CDK4/6 inhibitors in the same space.

There are some toxicities, especially hyperglycemia associated with the drug, but overall, it was able to be tolerated. And despite the fact that it did not reach the significance in overall survival, it trended in that way, and there was a clear progression to survival, so it still fits into a worthwhile discussion in treatment of patients with metastatic breast cancer.

Jamie DePolo: Sure. Definitely. Definitely encouraging results. As you said, not necessarily statistically significant in overall survival, but I think if I had been diagnosed with metastatic disease that had that particular type of genetic mutation, I would be encouraged by those results.

Dr. Michael Method: Thank you, and I do agree. It's certainly something that everyone with that mutation should now be, in the metastatic setting, considered for its use.

Moving on to another one of the late-breaking abstracts, and this was the late-breaking abstract #19, was a European trial that was sponsored by GEICAM, one of the large Spanish cooperative groups, and this is called the FLIPPER study.

This particular study looked at two different groups of patients that had endocrine-sensitive breast cancer: one that were stage IV in the first-line treatment, and another group that were those patients that actually recurred after 5 years of an endocrine therapy use in the metastatic setting.

And in this trial, they were able to actually demonstrate a significant progression-free survival that was particularly important in those patients that had de novo metastatic breast cancer, meaning that they had stage IV breast cancer at the time of diagnosis. So, all those patients had not seen any endocrine therapy, and those patients actually derived a significant benefit with an overall response rate of 68.3% versus 42.2% in that patient population.

And while this was only a phase 2 clinical trial, it added to the body of evidence confirming the benefit of the use of this class of drugs that we talked about in the beginning, which are the CDK4/6 inhibitors, in those patients with hormone-receptor-positive, HER2-negative breast cancer.

Jamie DePolo: I just want to clarify, when you started talking about the study, you said it was endocrine-sensitive. Does that mean hormone-receptor-positive breast cancer? I just want to make sure that’s clear for everybody.

Dr. Michael Method: No. That’s a great question, and thank you for asking. So, when we talk about hormone-receptor-positive, HER2-negative breast cancer, we are talking about a patient population that has the potential [to], or will, respond to endocrine therapy of some sort.

The reason we use the terms endocrine-sensitive versus endocrine resistant is that there are patients who have seen endocrine therapy previously to their treatment, whether that be in the early setting or in the metastatic setting, that redeveloped disease at the time of treatment at the time of treatment of that endocrine therapy or shortly thereafter. And in that patient population, we defined that it's endocrine resistant because they’ve seen endocrine therapy and then they’ve recurred shortly after that.

We're talking about that same class of patients, which are hormone-receptor-positive, HER2-negative, but that have not seen any endocrine therapy. And so by their very nature, they are, most of them, endocrine sensitive, whereas, as an example, there are specific treatments for those patients that have proven to be endocrine resistant. And when we talk about endocrine therapy, we are talking about those oral medications, such as tamoxifen, letrozole, anastrozole, so basically the aromatase inhibitors and the other selected estrogen receptor modifiers that we use in that space.

Jamie DePolo: So, in the FLIPPER study, the group of people that participated, they had metastatic disease that had not received any anti-estrogen, or as we call it, hormonal therapy, yet. So, this was looking to see whether these CDK4/6 inhibitors could be a good first treatment for metastatic disease?

Dr. Michael Method: That’s correct, and they included another patient population that actually were late recurrences. So, these are patients that actually had early breast cancer, were treated with their 5 years of endocrine therapy, as you described, and then several years after that — so they did not meet the criteria of endocrine resistance, because they didn't recur on or shortly after, so, they were a distant recurrence after it — so, that patient population was still endocrine sensitive, because they didn’t recur while on or shortly after the therapy. And so, those two populations were looked at. And in the FLIPPER study, the population that benefited most was the advanced early, so those patients that were diagnosed with stage IV endocrine, or hormone-receptor-positive breast cancer that had metastasized and had never been treated with any endocrine therapy.

Jamie DePolo: Okay. Very good to know, then. Very good to know. Okay. Was there any other studies that you thought were particularly interesting?

Dr. Michael Method: Yes. Yes, there were several. And I think we can probably move to the triple-negative patient population. Again, another very difficult to treat population. So, these are breast cancer patients and breast cancers that do not have any estrogen or progesterone or HER2/neu expressions. So, we call them triple-negative breast cancers, and by their very nature, they tend to be the most aggressive types of breast cancers that we treat.

This patient population was studied in several trials, actually, that were looked at at the ESMO Congress, and one was called the IMpassion131 trial, and the other was an additional IMpassion trial that was the 031 trial.

Both of these trials actually deserve a lot of attention, primarily because this is the patient population in breast cancer that seems to benefit the most from immunotherapy. And so both of these trials actually look at the use of immunotherapy in combination with chemotherapy, looking at the potential benefit.

One of the immunotherapy treatments, atezolizumab, which has been studied previously in metastatic triple-negative breast cancer, has been shown in combination with chemotherapy to be of significant benefit.

The two trials that actually looked at this congress were in the what we would call neoadjuvant setting, meaning up front, at the beginning, once diagnosed. And this would be prior to surgery.

And the interesting thing that was looked at in this trial was there are two combinations that were looked at using the same base drug but in different formulations. And that would be Taxol, or paclitaxel, and this other type of taxane that we have called nab-paclitaxel, which is just simply the same drug but it's actually placed into a liposome so that the side effects and toxicities and hypersensitivity problems around it are reduced. It's a more expensive drug, but it actually has some benefits.

And both were studied, actually, in this space. What's very interesting is the Taxol, which was not in the liposome — so, the regular Taxol, which is today the less expensive, perhaps more available Taxol — did not benefit with the addition of atezolizumab in the neoadjuvant setting and treatment. However, the nabpaclitaxel did, and that was the IMpassion031 trial presented by Nadia Harbeck at the Congress.

And in that trial, they actually looked at stage II and III triple-negative breast cancers that received neoadjuvant chemotherapy in combination with this immunotherapy. And in that patient population, the pathological complete response rate — and just to explain that, when you give treatment, the goal would be to eliminate the cancer. That doesn’t always happen, and oftentimes you have to perform surgery to remove the remaining cancer after you give it before surgery. The measure of success and outcome of triple-negative breast cancer is correlated very strongly to the ability to reach that pathological complete response rate; that is, no tumor left after chemotherapy.

The pathological complete response rate was increased from 40% to nearly 60% in the patient population that received the immunotherapy. And in the patients that actually had the immunotherapy marker — which many of you might have heard, which is called PD-L1-positive patients, which is a measure of an immune marker that suggests response to these immune drugs — that difference was 70% versus 50%. And that portends an excellent outcome in this patient population.

So, this, in fact, was a hugely important presentation and set of data that was presented, basically suggesting that the addition of an immunotherapy in the PD-L1-positive patient population had a very significant improvement in the pathological complete response rate, and the expectation would be in the overall benefit and survival of that patient population.

Jamie DePolo: Thanks for bringing that up. I do have a question. Because of the difference in the results, it seems to me — now I am not a researcher — but there was a difference in the type of chemotherapy that the immunotherapy — and I'll just say the brand name is Tecentriq, because I think a lot of our audience may know it that way. And in one case it was combined with Taxol [chemical name: paclitaxel] and in one case it was combined with the Abraxane [chemical name: nab-paclitaxel]. And when it was combined with the Abraxane the results were much more positive than when it was combined with Taxol.

So, to me, that’s very interesting, and I'm not sure if you want to talk about it. I know it generated a lot of discussion at the conference, people trying to figure out why. Was it just the difference in chemotherapy? Was there a slight difference, maybe, in the people that participated? So, I'm sure that’s going to generate a lot of discussion. I didn’t know if you had any thoughts on the differences in the outcomes.

Dr. Michael Method: No. I think that’s a really great question. As you know, comparable trials, side by side, is really unfortunately not possible, and I think all of the potential explanations that you gave are possible. You know, patient population, differences in risk factors, adherence to drug, et cetera.

One of the things that is oftentimes required with the use of Taxol, that particular brand product, is that we routinely give steroids to that patient population to minimize the risk of hypersensitivity, because that can develop in a number of patients. So it's a routine treatment. And the question that arose in addition to the ones you mention, is by giving steroids, are you inhibiting, preventing, somehow influencing the impact that an immunotherapy would have on the treatment at that time. And so I think that’s, in addition to the ones you mentioned, one of the ones that’s currently being thought of, and perhaps is being considered. But it is a question, and I can honestly say that I don’t have THE answer, but I think there are several potential answers.

Jamie DePolo: Okay. Yeah. Thank you for helping us understand that. Were there other studies that you thought were particularly notable?

Dr. Michael Method: Well, I do have one more that I think, really, was something of importance for everyone there listening. And that was the mini-oral presentation 167, and it was entitled “Longitudinal evaluation of serum assessed non-adherence to tamoxifen (TAM) among premenopausal patients (pts) in the prospective multicenter CANTO cohort.” And so, why this is a long title and so important — and this was presented by Dr. Pistilli from France — but this is critical in that adherence to endocrine therapy for the length of time that women have to endure the side effects is hugely important. And when we talk about risk/benefit, we have to understand that when we even look at the benefit associated with chemotherapy, radiation therapy, surgery, and endocrine therapy, it may be that one of the most important parts of an individual's treatment in this patient population — and again, the hormone-receptor-positive, HER2-negative population — is that endocrine therapy.

And when we looked at this trial — and this was a follow-up on the initial trial that looked at 1 year following treatment initiation — at that point, 1 in 6 women had discontinued their endocrine therapy or were not adherent. At this point, at the 3-year mark, 38.5% of patients actually were nonadherent.

And there were many reasons why they were not adherent, but when we look at the publication, actually, that was available at the time — the lead author was Ann Partridge, and we looked at what that meant for disease-free survival in that patient population — if at 3 years you were nonadherent, your risk of having recurrent disease was increased by a factor 2.3, or a multiple of 2.3, over those who actually had continued their therapy.

And while we all understand there are lots of reasons for discontinuation — it's miserable. You have bone aches and muscle aches. You have hot flashes, and there's lots of reasons why. I think what this tells us, and why this is so important, is because this tells us that we, those of us taking care of patients, need to do a better job of two things. One is communicating the benefit that’s associated with this treatment, and then helping the patient, you, through that treatment so that you can gain that benefit that is, in fact, significant for you and for your outcome.

And so, I just found this to be tremendously important. Something that we need to focus on, and really focus on our efforts on having patients tolerate their endocrine therapy moving forward, how can we help that? And fortunately, in today's day, we have several alternatives to that, as far as types of medications we can offer. Some have different side effect profiles than others. But also, emphasizing the benefit that can occur so that patients actually have the motivation and incentive to endure what is sometimes a very uncomfortable and difficult time.

Jamie DePolo: Yes. Thank you for that, and what I would add is we do get, on our site, many, many comments, people talking about the side effects of hormonal therapy, whether it's tamoxifen or an aromatase inhibitor — hot flashes, joint pain, all those kinds of things. And I know, as you said, it can be miserable. I guess, I would add that I would strongly urge anyone who's having those side effects to talk to their doctor, because there are treatments available to help ease some of those side effects. I don’t know that they can ever go away completely, but I do know there are things that can make them much less painful.

And so, I strongly agree with you. I'm glad you brought that up.

Dr. Michael Method: No, and I absolutely agree with you, is that there are things that can be done, and you should bring those to the attention of your physician rather than stopping the medication. It's in your best interest to continue, but to find a way to either tolerate it or find an alternative medication that would do the same thing. And there are several alternatives that we can turn to. So, in both cases, I think you and I are aligned that this is critical for our patients and hugely important to encourage our patients to talk to us about those symptoms that sometimes they don’t feel are important, but we now know how important they are.

Jamie DePolo: Absolutely. Dr. Method, thank you so much. This has been so helpful. Even though ESMO was virtual, I kind of feel like I was there now, so I really appreciate your time.

Dr. Michael Method: My pleasure, and thank you.

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