Verzenio Improves Overall Survival in Hormone Receptor-Positive, HER2-Negative, Advanced Stage Breast Cancer

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Jamie DePolo: Hello, thanks for listening. Dr. Matthew Goetz is professor of oncology and pharmacology at the Mayo Clinic. At the European Society for Medical Oncology Congress 2022, Dr. Goetz presented interim overall survival results for the MONARCH 3 study, which is comparing the targeted therapy Verzenio plus an aromatase inhibitor to an aromatase inhibitor alone to treat hormone receptor-positive, HER2-negative, advanced-stage breast cancer. He joins us to discuss the results. Dr. Goetz, welcome to the podcast.

Dr. Matthew Goetz: Thank you Jamie. I look forward to speaking with you.

Jamie DePolo: So, to start just so we’re all kind of on the same page and everybody knows what we’re talking about, could you tell us what kind of treatment Verzenio is, how it works, and how its currently used?

Dr. Matthew Goetz: So, Verzenio or in other words referred to as abemaciclib, which is the generic name, is an oral CDK4/6 inhibitor. It is a medication that is currently approved for the treatment of estrogen receptor-positive or hormone receptor-positive HER2-negative breast cancer in patients who have metastatic disease. It’s approved right now in the U.S. and globally for patients in the first-line and second-line setting and in that situation is approved in combination with hormonal therapy. 

It’s also approved as monotherapy in patients who’ve had prior progression on chemotherapy as well as hormonal therapy. Then more recently in the last year or so, it was approved in the U.S. by the FDA in the adjuvant setting for patients with a high risk, meaning high stage ER-positive, HER2-negative breast cancer in the adjuvant setting.

Jamie DePolo: Okay. Thank you. So, could you summarize the MONARCH 3 study for us. What were you looking at? What were you trying to do with that?

Dr. Matthew Goetz: So, the MONARCH 3 was a clinical trial testing whether the addition of an abemaciclib to standard hormonal therapy would improve progression-free survival. Progression-free survival in this situation is a standard way that we assess efficacy of drugs in the metastatic setting. There are three CDK4/6 inhibitors that are out there. The first one to market was palbociclib, sometimes referred to as Ibrance. Then ribociclib was the second, and abemaciclib was the third. 

Really in these trials that have tested the CDK4/6 inhibitors, when we’ve looked at the outcome of progression-free survival and we look across the trials that have tested the CDK4/6 inhibitors, we’ve seen that the benefit in terms of progression-free survival seems really quite the same. So, most investigators have said, well, these drugs are interchangeable. You can simply pick which one you want based on side effects. 

Perhaps some particular insurance companies have developed contracts with a particular CDK4/6 inhibitor, but they’re really all the same and that’s kind of what people have thought. What has been emerging is the fact that when we’ve looked at the secondary end points of overall survival -- so now we’re simply asking the question of do you live longer if you take these drugs than if you don’t take the drug -- which is quite a bit different question but a very important question. And the answer is we’ve been getting conflicting data. 

So, with the drug ribociclib, we have very consistent data in the first- and second-line settings. Both in pre-menopausal as well as in post-menopausal patients. The addition of ribociclib to hormonal therapy improves overall survival. With abemaciclib, we’ve had one trial report out that in the second-line setting, which is the MONARCH 2 trial, demonstrating that abemaciclib when added to hormonal therapy, in this case fulvestrant, improved not just progression free survival but it also improved overall survival.

In contrast, for palbociclib, we have not yet seen the addition of palbociclib to hormonal therapy improves overall survival, either in the PALOMA 1 trial or the PALOMA 3 trial. The major first line trial that was just recently reported out for palbociclib back at ASCO really hit the news and created even more controversy because that trial showed that the addition of palbociclib to, in this case to standard hormonal therapy or letrozole, did not improve overall survival.

So, with that in mind, you know, the data for MONARCH 3, which is the trial that I reported at ESMO, have been eagerly awaited because there’s this controversy now. Some of these drugs appear to improve survival. Some of them do not. And so, with that in mind, what I presented at ESMO was the second planned interim overall survival for this particular compound.

And so, stepping back, this trial, the results of this trial, has already shown that the addition of abemaciclib to hormonal therapy improves progression-free survival. So, now what we’re reporting is the second interim overall survival analysis. So, that’s the background here.

Jamie DePolo: Okay. Before we get to the results, I just want to ask one question. Sorry to interrupt. The difference between progression-free survival and overall survival to me, and I’m not a scientist, if a drug improved progression-free survival, it would seem that it would probably improve overall survival, but it doesn’t seem like that’s the case. So, could you I guess help me understand why we would see that disconnect.

Dr. Matthew Goetz: Sure. So, progression-free survival is something that measures the time until a particular event occurs, and in this situation an event typically is going to mean progression of disease. So, I’ll give you an example. A patient is taking a medication. They have a diagnosis of metastatic cancer and they’re doing well and approximately one year later, their cancer progresses. So, that would be considered an event. 

Now we know that for the treatment of ER-positive, HER2-negative breast cancer that you might have progressive disease, but there are many other therapies that might be available for an individual to take. That could include chemotherapy. It could include a drug like a PI3 kinase inhibitor if you happen to have a PIK3CA mutation. It could be an antibody drug conjugate. So, there are many other drugs.

So, progression-free survival is measuring time to that first event. Now sometimes that first event could be death but that’s fairly rare. That first event is usually going to be a progression event. So, we would expect then that gain, so in this case the CDK4/6 inhibitors have a large progression-free survival gain, we would expect as you just said that that gain would continue to be there all the way out to death. So, we would not expect then that the curves would come back together.

And so, in this situation, why might the curves come back together? So, why might progression-free survival gain be lost? Well, it’s possible that patients are crossing over and receiving the CDK4/6 inhibitor that they didn’t get when they were originally randomized. That’s a possibility. There may be other issues as well, but I would say in general when we run trials, we would expect that the PFS advantage will translate into an overall survival advantage.

Jamie DePolo: Okay. And is it possible like the cancer could become resistant to the particular medicine and that would sort of bring the curves back together?

Dr. Matthew Goetz: I think that’s a real good question and that might be, for example, in the case of a drug that’s working while you’re taking it, it’s possible that the time that the cancer cells become resistant to a medication, that resistant phenotype can be more aggressive than when the cancer was originally diagnosed. And so, that’s a possibility in that scenario that all of a sudden, the cancer cells begin to grow faster. They’re more aggressive and then therefore when a medication is stopped, you sort of then lose the benefit that was seen while you were taking the medication. 

Jamie DePolo: Okay. Thank you. That’s very helpful. So, now getting back to MONARCH 3, could you summarize the results for us. What did you discover?

Dr. Matthew Goetz: So, what we found was that the addition of abemaciclib to standard hormonal therapy improved overall survival in the intent-to-treat population by about 12 months. So, in the patients that were receiving the placebo plus aromatase inhibitor arm, so these patients were receiving either letrozole plus anastrozole, the median survival was 54 months. 

In those patients that received the aromatase inhibitor plus abemaciclib, the median overall survival was 67 months, and this corresponded to a hazard ratio of 0.754, which essentially means that there is approximately a 24% improvement in the overall survival for patients who received abemaciclib versus placebo. 

Now the p value here was .0301 and importantly, because this was an interim analysis for overall survival, the stopping boundary was not crossed. And so, what does that mean? That means that even though the p-value in this case is less than .05 that because the stopping boundary was not crossed, we did not stop the study conduct and we will continue to follow patients until we get the final overall survival results. But I think what we can say is that these data are maturing quite favorably and we’re seeing as I said earlier a difference in median overall survival by over 12 months.

The second thing that we looked at was also preplanned and this is looking at overall survival in those patients with visceral disease. Patients who have visceral disease we know have a higher risk for progression. They tend to have a worse outcome and specifically in those patients who have liver metastases. This is something that’s been known for quite some time.

One of the things that has been seen with the drug abemaciclib is that this medication appears to work particularly well in patients who have estrogen receptor-positive or hormone receptor-positive breast cancer that is resistant or tends to be more resistant to standard hormonal therapy. And so, we were quite interested to see whether the addition of abemaciclib to standard hormonal therapy could improve outcomes in this group of patients with more aggressive disease. 

And indeed, what we found was that the addition of abemaciclib to hormonal therapy improved overall survival from 48.8 months up to 65.1 months in this group of patients with visceral disease, and this corresponded to about a 29% improvement in overall survival with a p-value of .0392. Again, this did not cross the boundary for what we would refer to as statistical significance because it’s at an early time, but again, we would say these data are maturing very favorably and I would say that in my estimation seeing a greater than 16-month improvement in overall survival in this group of patients with very aggressive disease is really quite impressive.

Jamie DePolo: It sounds like it. I do want to clarify just so everybody knows, visceral disease, you mentioned the liver but that could also be the lungs or any other sort of soft organ, am I understanding that correctly?

Dr. Matthew Goetz: That’s right. So, patients who have visceral disease we typically either think of either lung or liver. Now it can include people that have bone, but they would have to have bone plus liver or bone plus lung.

Jamie DePolo: Okay. Thank you. As far as I know, there are no studies that have compared the CDK4/6 inhibitors head-to-head. Is that correct?

Dr. Matthew Goetz: That’s correct. There is one planned study that actually…planned meaning I believe it’s already activated in Europe. This is the HARMONIA study, which is looking at a subset of patients with hormone receptor-positive, HER2-negative breast cancer who have this so-called HER2-enriched group of ER-positive, HER2-negative breast cancer. And in that trial they’re making a direct comparison of ribociclib versus palbociclib. And so, that’s really the only head-to-head trial that I am aware of at this time, and again, it’s restricted to a subset of patients.

Jamie DePolo: Okay. So, earlier in the podcast you said initially after the results from the first studies on CDK4/6 inhibitors came in, most doctors thought okay these are interchangeable. Now we’re getting these overall survival results, it sounds like they’re not so interchangeable. So, what do these latest results from MONARCH 3, what do they mean for me if I’m diagnosed with metastatic, hormone receptor-positive, HER2-negative breast cancer? Can you sort of put this in context for us?

Dr. Matthew Goetz: So, this is really the million dollar question that we have to address. When we look at the CDK4/6 inhibitors, one of the things that I state when I’m commonly giving talks upon this subject and when I’m speaking to other investigators is we should never really look at one trial in isolation. 

So, for example, had we only the data from PALOMA 2 where we saw that there was again a large improvement in progression-free survival, but no improvement in overall survival, I think most of us would be quite comfortable in saying well, overall survival was not a primary endpoint. It was a secondary endpoint and there are some reasons why overall survival may not be improved with palbociclib, so therefore, this shouldn’t change our practice. 

But I think what we have to do is we have to look at the data in its entirety. Palbociclib has been a very good drug and we’ve used it for quite some time, but why we are not seeing an improvement in overall survival certainly is curious. But we have not seen improvement in overall survival either in PALOMA 1, PALOMA 2 or PALOMA 3, and furthermore, when the drug was tested in the adjuvant setting, in PENELOPE and PALLAS there was no improvement in an invasive disease-free survival. 

So, that tells us that this drug seems to be working when you take it, but once you stop taking it you sort of lose the benefit, if I were to use that terminology. So, again, as we look at ribociclib we see the PFS advantage translated into an improvement in overall survival and we’re beginning to clearly see that with the drug abemaciclib. Certainly for MONARCH 2. 

For MONARCH 3 of course, we have to wait for the final overall survival data because right now we haven’t reached statistical significance, but everybody can see that the data are really maturing quite favorably, and of course with abemaciclib we know that the drug works in the adjuvant setting. So, it’s really improving outcomes there. 

So, what is the take-home point? I tell my colleagues and patients that when I’m having a conversation with patients, I share them the data and when I share these data to patients, they typically say I want to have access to a drug that is improving overall survival. So, we generally will either utilize ribociclib or abemaciclib. 

Jamie DePolo: And are there side effects? I believe the side effects are fairly similar but are there side effect differences between those two that could sway someone’s choice?

Dr. Matthew Goetz: There definitely are. So, you know, abemaciclib is a drug that is given continuously. So, that is a, if we think a little bit about the side effect profile of CDK4/6 inhibitors, one of the side effects that you can see is neutropenia or a low white blood cell count, and for the drug ribociclib and palbociclib, the drug is given discontinuously, so that means you take it for 21 days and then you have a break sort of to give your neutrophils, if you will, a bit of a break, whereas abemaciclib is given continuously. 

So, we tend to see a little bit less issues with neutropenia and in general myelosuppression, which means suppression of the white blood cells, platelets, etc. With the drug abemaciclib, it has a unique side effect and that’s diarrhea. When we were first beginning to study abemaciclib in some of our earlier-phase studies, you know, diarrhea was a really major issue for patients, but what we’ve come to discover over the last three, four, five years is that its quite manageable. 

It is manageable with either using the drug Imodium or with dose reductions. In most people, after a period of time, can have the diarrhea managed appropriately. So, I think the diarrhea is certainly a unique side effect of abemaciclib, but again it can be managed. There are some other side effects with these drugs that tend to be common across them. Certainly, we see some fatigue. Occasionally we’ll see some hair loss, mild hair loss. And so, these are present. Sometimes we might see a bit of anemia. 

A rare side effect that is seen with all of the CDK4/6 inhibitors is there’s a slight risk of blood clots that may be magnified if you take in this case a drug like abemaciclib along with tamoxifen, which in itself has a slight risk for blood clots. So, we know about some of these side effects, but in general, most of the time they’re manageable.

Jamie DePolo: Okay. So, it sounds like maybe the side effects even though they’re different they wouldn’t be the deciding factor.

Dr. Matthew Goetz: They’re not the deciding factor up front I think, unless for example I have a patient that has an underlying history of inflammatory bowel disease where there’s an issue there with the gut. I might choose a drug that is not going to have diarrhea issues. But again, if we run into a particular side effect, we can move to the other CDK4/6 inhibitor.

Jamie DePolo: Okay. So, then I guess the for me the bottom line is how do you choose or how do you and your patients choose together? It sounds like your patients would want to go for the CDK4/6 inhibitor that improves survival, and you have two of them. Is it really just okay I’m going to try this one or I’m going to try that one?

Dr. Matthew Goetz: Yeah. So, I think that that’s a great question and the answer is right now we don’t have that head-to-head data. And so, one of the additional pieces of the puzzle I think is going to be helpful for us is when we get the results of the NATALEE trial. The NATALEE trial is a trial looking at ribociclib in the adjuvant setting and I think if we look and the NATALEE trial is positive, then we can look across and say listen, ribociclib improves outcomes in every setting. That is in the metastatic and the early-stage setting. 

With the drug abemaciclib, the pieces of the puzzle are coming together as well. It's improving outcomes in the metastatic and in the adjuvant setting. So, my sense here in my conversations with patients are going to be, I’m going to choose a drug that has a proven survival advantage and probably individualize based on the patient’s preferences and potential toxicity profiles, their past medical history, and knowing that if they run into problems we can switch to another one. 

Jamie DePolo: Okay. Dr. Goetz, thank you so much. This has been so helpful and informative. I appreciate your time.

Dr. Matthew Goetz: You’re welcome. Thank you.