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Verzenio Reduces Recurrence Risk for Certain Early-Stage Breast Cancers
Stephen Johnston, M.D., Ph.D.
September 21, 2020

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Dr. Stephen Johnston is professor of breast cancer medicine and consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London.

At the European Society for Medical Oncology Virtual Congress 2020, Dr. Johnston presented results from the monarchE trial. This study compared treating people diagnosed with early-stage hormone-receptor-positive, HER2-negative breast cancer with a high risk of recurrence with either standard hormonal therapy after surgery or two years of Verzenio (chemical name: abemaciclib) in addition to standard hormonal therapy.

Listen to the podcast to hear Dr. Johnston explain:

  • the characteristics that make early-stage hormone-receptor-positive, HER2-negative breast cancer have a high risk of recurrence
  • an overview of the study and its early results
  • side effects caused by Verzenio seen in the study
  • the future of using Verzenio to treat early-stage hormone-receptor-positive, HER2-negative breast cancer with a high risk of recurrence

Running time: 27:08

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

Welcome to the 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, senior editor Jamie DePolo.

Jamie DePolo: Hello! Thanks for listening. Dr. Stephen Johnston is a professor of breast cancer medicine and consultant medical oncologist at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research in London.

At the European Society for Medical Oncology Virtual Congress 2020, Dr. Johnston presented results from the monarchE trial. This study compared treating people diagnosed with early-stage, hormone-receptor-positive, HER2-negative breast cancer with a high risk of recurrence with either standard hormonal therapy after surgery or adding 2 years of Verzenio, which has the chemical name abemaciclib, to the standard hormonal therapy. He joins us today to talk about the results.

Dr. Johnston, welcome to the podcast.

Dr. Stephen Johnston: Thank you.

Jamie DePolo: So first, could you tell us the characteristics of this particular type of cancer — early-stage, hormone-receptor-positive, HER2-negative — that make it have a high risk of recurrence?

Dr. Stephen Johnston: Sure. We designed this trial really targeting those patients that we know still have up to a 20% risk of their cancer coming back within the first 5 years, despite everything that we give them in terms of the standard surgery, radiotherapy, chemotherapy.

So these are node-positive patients, but they are node-positive patients with extra risk. And that’s driven by either the number of nodes, so we included patients who had 4 or more lymph nodes, and that was actually 60% of the patient population, or if they had 1 to 3 nodes involved, they had to have 1 of 3 other risk factors in their tumor that we know gave them that increased risk. And that was either a big tumor, at least 5 cm or more, so T3; a high-grade tumor, so grade 3; or if they didn’t have either of those they had to have an increased what we call cell proliferation, a marker called Ki-67, that tells us if the cancer is dividing more quickly.

So all those characteristics we calculated looking at some big data sets from the American Group, the NSABP, a West German group that had looked at nodes and grade, and calculated that yes, despite the best chemotherapy and the best treatment, these patients, if they had these features, they still have a chance of the cancer coming [back] of up to 20% in the first 5 years.

So that was our background for the control arm of which we needed to see whether we could improve upon, because these patients may have more aggressive cancer, it might be resistant to hormone treatment, so hence the reason to add something in that we know can overcome that.

So that was really the premise for the design, to really target a group with what we call an unmet need. And indeed, over 95% of the patients had received chemotherapy, many of them before surgery, because that’s often what we do if people have high, large tumors with nodes involved. So that was roughly the population that we pitched the study at.

Jamie DePolo: Okay. And I know that Verzenio, right now, at least in the U.S., is really only approved to treat metastatic disease. Why did you think that Verzenio might help reduce this risk of recurrence?

Dr. Stephen Johnston: Sure. So abemaciclib, or Verzenio, is approved in only metastatic disease both in the U.S. and in Europe and the rest of the world based on trials called MONARCH 2 and MONARCH 3.

MONARCH 3 looked in combination with an aromatase inhibitor if the cancer came back as metastatic disease, and showed significant improvement of control of the cancer compared to hormone treatment alone.

But MONARCH 2 was really interesting, because that looked at patients whose cancer was coming back on endocrine therapy, so they previously had an aromatase inhibitor, and either the cancer came back while they were on their aromatase inhibitor or if they had progressed having had that as treatment for their metastatic disease. And in that particular trial where abemaciclib was added to a different hormone treatment, fulvestrant, not only did it improve the control of the cancer, so more cancers shrunk down and were controlled for longer, it also improved the survival of patients in metastatic disease by an average of over 9 months. Some patients were staying on treatment for very long periods of time.

So we knew in advanced disease that the drug had activity, particularly in patients where the cancer was showing features of endocrine resistance and spreading potentially to areas such as certain sites of metastasis in the liver, and it had very substantial activity in that scenario.

So if, in the early breast cancer setting, we had a group of patients that were potentially at great risk of their cancer coming back on hormone treatment and potentially spreading to other sites of the body, that’s where we thought the drug had shown real promise in advanced breast cancer, and it was worth testing in the early breast cancer setting if it would prevent the cancer from coming back, particularly in the early years.

Jamie DePolo: Okay. Could you give us an overview of the results then?

Dr. Stephen Johnston: Sure. So this was an analysis that was a preplanned interim analysis driven by what we call how many events. So how many in the trial of the two arms overall, how many recurrences of cancer had started to occur? So we had to have at least 75% of the total planned events, which was 390, and we had about 320 events when the analysis was done. So that allowed the data to be looked at by the independent data monitoring committee and determine whether we had had a positive trial or not.

And what the results show is that at this time point, there was a 25% reduction in the risk of invasive disease developing, whether that’s a recurrence of the cancer locally, but usually in terms of spread to other sites. And if we looked just at what we call distant relapse-free survival, so that’s whether the cancer had gone to a second site such as the bone, liver, or whatever, there was a 28% reduction in risk. And this was really at the point of 2 years where we saw this difference developing, that’s where the curves started to separate. And the biggest reduction was in the risk of bone and liver metastases, which again, was what we suspected might happen, that we would have an impact on preventing metastatic sites of disease developing in an early time frame.

So it is an early analysis. The median what we call follow-up, so how long we’ve been following patients overall, is 15 months. This is a 5,500 patient trial, so it’s a big trial, and more analysis will continue. But this early impact is impressive, and that’s why we’ve announced the results, because it has met what we call the primary endpoint of the trial and shown this 25% reduction at an early stage.

Jamie DePolo: Okay. Thank you. And how long do you plan to follow the people in the study overall?

Dr. Stephen Johnston: Well, what we’re always interested in these early breast cancer trials is whether ultimately it cures more patients, the overall survival. At the moment we’re just measuring what we call disease-free survival, how long patients are free of their cancer coming back. But ultimately we want to know that we cure more patients. And to do that, we will probably need to follow the trial through to 2027 or 2029, so at least for another 7 to 8 years, before we would get an impact on the overall survival.

Also, we know that hormone-positive breast cancer, it’s not just the early recurrences, but can the cancer come back at a later stage? So we want to know whether 2 years of the drug will impact and stop the cancer from coming back 5, 6, 7, 8 years later, and we’re far too early to know that. So it’s really important that patients in the trial continue to be followed and monitored. It was a Herculean effort of over 600 hospitals in 38 countries around the world in every continent. I spoke to all the investigators last week at some webinar meetings to give them the results and really thank them and their patients and their staff, but really encourage them that we must continue to follow patients in this trial, because we don’t yet know what the level of further ongoing impact will be. And also what the ongoing safety of the drug is, which is what is really also important in these early breast cancer studies.

Jamie DePolo: Sure. and I’m also curious because I know I’ve seen other studies saying that a lot of women stop taking their hormonal therapy early, they don’t complete the full 5 years. Now I know they only have to take the Verzenio for 2 years, but I guess I’m wondering if someone stops taking the hormonal therapy early, are they out of the trial and do you think that… clearly that’s going to affect the result somehow.

Dr. Stephen Johnston: Yeah. So at the moment the patients in this study were highly motivated to go into the trial because they knew they had a big risk, and their compliance was really excellent. Yes, now, there were some discontinuations. We had 16% of patients who discontinued the abemaciclib either due to adverse events that couldn’t be managed by dose reductions or they withdrew consent or their cancer had obviously progressed. But some other studies have much higher discontinuation rates.

The endocrine-therapy-alone arm, patients who were just taking hormone therapy alone, I think it was less than 1% who discontinued. And again, this is an early analysis, but it also attests to a really interesting observation that we found in the safety data when we looked at what the main side effect of hormone treatment is.

Yes, we were worried about the side effects of abemaciclib. There were no new signals, and we know about the main side effects, which relate to diarrhea and how to manage it. But with hormone treatment, the main side effect is hot flushes and joint symptoms, arthralgia. And this was the most common adverse event in the hormone-alone therapy arm, 31% of patients had some form of arthralgia, 21% had hot flush. But really interestingly, when abemaciclib was added to that, we had a 30% reduction in these hormone-like side effects.

Now, some people might have thought that was a play of chance, and they were worried about the other side effects of abemaciclib so they didn’t report their joint symptoms and so on. But it’s an observation we’ve seen before in another neoadjuvant trial of palbociclib and hormone treatment that we reported on a couple of years ago. And we saw the same 30% reduction in hot flushes and joint symptoms. So there may well be a mechanism, an interaction of the CDK inhibitor and the hormone treatment to modulate or change some of the really troublesome side effects that we have with hormone therapies, particularly aromatase inhibitors. So that’s an observation and a hypothesis that we just have to look at in more detail.

But to answer your original question, adherence to therapy is important because if it has benefit it can only work if people take it. And so there was a lot of discussion at the ESMO meeting yesterday about discontinuations and whether or not that reduces the likelihood of treatment working. But in our trial the discontinuations of hormone therapy were very low.

Jamie DePolo: Okay. That sounds great. Thank you. I’m also curious, I’d like to talk a little bit about the chemotherapy. I know you said that about 95% of people in this study had previously been treated with chemo. Is there anything in the results that suggests that potentially a certain group could skip chemo and just have the Verzenio and the hormonal therapy, or because so many people in this study had previous chemo, it’s hard to tell?

Dr. Stephen Johnston: Yeah. I think, you know, when we were originally designing this trial 4-5 years ago, one of the really radical ideas we put on the table was, would we actually do a trial in high-risk early breast cancer and put this treatment up against chemo and say, “Can we do without chemo and use this treatment instead?”

It was rejected at the time as maybe far too radical, but it’s back on the table in people thinking now, particularly because in metastatic disease we’ve done two trials comparing CDK4/6 inhibitors to chemotherapy, one a Korean study called Young-PEARL, which showed that chemo was a bit better, the other one from the Spanish group showing that it was exactly the same.

So it’s back on the table, but this trial, because it was very high-risk patients, node positive — and high-risk node positive — then clinicians would’ve been very anxious and worried not to give chemotherapy. And so that’s why 95% had had chemo, 43% were premenopausal, and we had 37% who had neoadjuvant chemo before surgery. So that speaks to a higher risk, younger, often, patient population with big tumors and so clinicians are bound to still give chemo.

But despite the chemo, these patients in the control arm, 12% had relapsed by 2 years. That was well on target for the 20% relapsing at 5 years that we had designed the study around. So despite chemotherapy, these patients have unmet needs and high risk. And you have to then ask, well, if chemo didn’t solve the cancer for them, would we have been better to give this drug alone?

But at the moment this is an add-on after chemotherapy, where we know it synergizes and makes the hormone treatment better and overcomes hormone resistance. So that’s really why we designed it. But it’s a very good question. Can we even challenge chemotherapy? But we’ll have to do other trials to confirm that.

Jamie DePolo: Okay. And as sort of a side note, I noticed that men were allowed to be in this trial. Were there any men in the study?

Dr. Stephen Johnston: Yes, indeed there were. So there was about just under 1% of the trial had men in it, but to be precise it was 21 men in the abemaciclib arm, 15 men in the endocrine therapy-alone arm.

So we know that 1% of breast cancer is male. There was no reason to deny men in the trial access to the drug. It was 0.7 and 0.5% respectively in the arms that were male. So the numbers are very, very small, so you can’t draw any conclusions, but there was no reason to exclude them. We treat men who get recurrent breast cancer with these drugs, so there was no reason we felt to exclude them in the early breast cancer trial.

Jamie DePolo: Okay. And so following up on your comment about 40% of the people in the study were premenopausal, were they taking tamoxifen with ovarian suppression? Because I know that for the approval of Verzenio, it’s usually given with an aromatase inhibitor. So I wondered if you saw any differences in how effective it was?

Dr. Stephen Johnston: Sure. So in terms of the first hormone treatment that was given, 30% was tamoxifen, 70% was an aromatase inhibitor. But the women on tamoxifen, the number that got ovarian suppression as well was about 7%, and for those who had an aromatase inhibitor, the addition of ovarian suppression was about 14%.

Now, you might think that’s a relatively low number, but remember a lot of women in their 40s who might have had chemo are then put into menopause because of their chemotherapy, so they may not need ovarian suppression added in.

So again, there’s no reason why the drug doesn’t work with other endocrine therapy. Indeed at this ESMO meeting, there was a trial presented by my colleague Erika Hamilton in the U.S. for nextMONARCH, where tamoxifen and abemaciclib was compared to abemaciclib its own in 2 doses, and the tamoxifen and the abemaciclib was better. So we know that the combination is there.

We’re monitoring very closely some of the adverse events, because there’s a low incidence of venothrombotic events, and we know that can be a trouble with tamoxifen, and again, in the metastatic study, that they reported a number of patients who developed venothrombotic events. And we reported the data in the monarchE trial, the incidence of venothrombotic events is less than 2%. So the incidence is very low.

So that aside, in terms of safety indications, there’s no reason why you can’t combine this drug with any endocrine therapy, tamoxifen, aromatase inhibitor, or indeed fulvestrant in the metastatic setting. So approval is being sought now through the regulatory authorities, and it will be aligned to the trial. But basically, if tamoxifen is the drug of choice in premenopausal women, that can be combined with abemaciclib and is known to be very effective.

Jamie DePolo: Okay. Thank you. And you mentioned some side effects. I believe diarrhea was the most common. So can you talk a little bit about that, how many people had it? How was it managed?

Dr. Stephen Johnston: Sure. So we know already from using abemaciclib in advanced disease, that diarrhea is the most common side effect, and we saw no new safety signals in the trial. So, diarrhea was the most frequent adverse event. In terms of the overall frequency, yes, up to 80% get some form of diarrhea, but the vast majority is grade 1 or 2, so less than 7%, I think it was, had what we call grade 3 diarrhea, which is the most troublesome form.

Now the key thing is education of both the oncologist and the patient to act quickly. So the median onset, in other words how soon the diarrhea comes, is within 8 days, so it’s in the first week or so, and it lasts on average 5 to 6 days. So it’s short-lived, and the key thing is to give antidiarrheal medication, loperamide, as soon as the first loose stool occurs. And then if necessary, omit the dose of abemaciclib for a few days until the symptoms settle and/or dose reduce.

Now, in terms of dose reductions, 40% of patients had a reduction of their dose. And we know from, again, advanced disease that the lower dose, 100 mg twice a day, is just as effective as 150 mg twice-a-day dose. It has the same benefit. You find the dose that the patient is suited to in terms of their side effects, and that then allows the patients to stay on study. And less than 5% of the abemaciclib patients had to actually come off the trial for diarrhea.

So you essentially adjust, give the anti-diarrheal medication, and maybe omit a dose but adjust it for a few days, reduce the dose, and then patients can stay on the drug. And that’s really the key learning in terms of education for both clinicians and patients, and once they know that, because it occurs very early, that allows them to stop. So we showed the data about the diarrhea severity and frequency over time, and we know that it significantly reduces in frequency and severity over time. And after 3 months, the majority of patients have no diarrhea events, and if they do it’s just mild, grade 1, with intermittent loperamide being used to help it. So it is manageable. It just requires a bit of education to know how to interact.

Jamie DePolo: Okay. Thank you. I know the CDK4/6 inhibitors were required to put a warning about interstitial lung disease within the last year. Did you see anything like that in this trial?

Dr. Stephen Johnston: Sure. It was an FDA-mandated warning that’s gone on to all the CDK inhibitors, so it was an adverse event of interest that we followed. So in terms of ILD [interstitial lung disease], yes, there were events reported, but there were events reported in the endocrine therapy-alone arm.

So there were 1.2% of patients in the endocrine therapy alone [who] had some form of so-called interstitial lung disease versus 2.7% in the abemaciclib arm. Now in terms of what we call severe grade 3 interstitial lung disease where it’s definitely either radiological or symptomatic changes, the number of patients was 9, so 0.3%, with abemaciclib versus 1 with the endocrine therapy alone.

So really, in terms of severe ILD, it’s single digits in this 5,000-patient study. But we report in the paper and in the data the overall that were falling into some form of diagnosis of pneumonitis. But of interest, it occurred in the endocrine therapy alone arm as well.

Jamie DePolo: That is interesting. Well, thank you. So these results sound very positive. Again, they are early results. So where do we go from here? Obviously more research is necessary, but are we going to see a change in the use of Verzenio based on this research? Do we have to wait for the final results? What do you see in the future?

Dr. Stephen Johnston: Well, the sponsor company is submitting an application to the FDA in the States and the European Regulatory Authority because the trial met its endpoint, and therefore for these specific high-risk patients, so node-positive with these high-risk features who are at increased risk of recurrence up to 20% in the first 5 years, this offers a new treatment that can reduce that risk of recurrence by 25%, particularly in the first few years. And therefore there’s enough justification because this is a statistically robust and solid result that they can file for that. But it also tells us that we’re not sure yet whether this is a treatment for everybody, because there was another trial, the PALLAS trial with a different CDK inhibitor, ostensibly very similar design, but it included some node-negative patients, but some of these high-risk patients, where the trial was stopped because there was absolutely no benefit at all.

So it’s clear I think that there may be a very select group, and at this stage it might be those that we know are destined to recur early. They’re the unmet need, and they’re showing signs of endocrine resistance. And this is a drug that’s demonstrated its track record in reversing endocrine resistance.

What we want to do is now be a little bit more smart and look to see if we can find out that endocrine resistance in a wider group of early breast cancer patients. So there was a trial in the UK called POETIC where we gave aromatase inhibitors for 2 weeks before surgery and measured what we call Ki-67, which is a measure of proliferation. We’ve done that in this trial. We haven’t presented our data yet on the Ki-67, but if you give an aromatase inhibitor for 2 weeks before a lady has an operation and measure how fast the cells are dividing before and after that 2 weeks of treatment, if the cancer has a high proliferation and the levels drop right down, you know the hormone treatment’s working. And we know from the outcome that those patients are going to do very well when we follow them for 5 years.

But if your cancer doesn’t drop down, in other words the proliferation doesn’t change with letrozole, that tumor is showing innate primary resistance. And we know from the POETIC trial that those patients have a 20% chance of coming back in 5 years, exactly the same risk as the patients in the monarchE trial. And those are patients that may have smaller tumors, grade 2 tumors, nodes are negative, but their cells are primed to be resistant to the hormone treatment. And you can use a short exposure of an aromatase inhibitor to personalize and test that endocrine resistance in a simple way before surgery.

So we’ve designed a trial called POETIC-A, which will now take the study forward and select those patients not responding to an aromatase inhibitor for 2 weeks, and then randomize them to abemaciclib for 2 years or the control arm. Because this will now look for patients with biological risk of recurrence as opposed to clinical pathological risk of recurrence, which is big tumors, lots of nodes, which is what we did in this current trial.

So that will test the concept of whether you can really fine-tune for an individual patient their level of risk. And because these drugs are expensive, they’ve got side effects, and they’re not to be used by everybody, you really have to define those that benefit.

Coming back to monarchE, we’re doing a lot of what we call translational research. We’ve collected tumors and blood samples from all of the patients in the trial, and we’re going to be measuring lots of different things about their gene expression, the various biomarkers to learn more about who benefits and who doesn’t. So ultimately, I see in years to come, these drugs will be available, but they’ll be tailored to the patients that we’ve learned are the ones that really need it.

Jamie DePolo: That sounds very exciting. Dr. Johnston, thank you so much for joining us. This has been very, very educational. I appreciate your time.

Dr. Stephen Johnston: Okay. Thank you very much indeed.

Editor’s Note: On Oct. 12, 2021, the U.S. Food and Drug Administration (FDA) approved Verzenio in combination with either tamoxifen or an aromatase inhibitor after surgery to treat early-stage hormone-receptor-positive HER2-negative node-positive breast cancer with a high risk of recurrence (the cancer coming back) and a Ki-67 score of 20% or higher. Node-positive means cancer cells have been found in one or more lymph nodes. Ki-67 is a protein in cells that increases as they prepare to divide into new cells. A staining process can measure the percentage of tumor cells that are positive for Ki-67. The more positive cells there are, the more quickly they are dividing and forming new cells.

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