Kisqali Plus Femara Seems Best Option for Advanced-Stage Hormone-Receptor-Positive HER2-Negative Breast Cancer

Jamie DePolo: Hello, thanks for listening. Dr. Gabriel Hortobagyi is a professor of breast medical oncology at the University of Texas MD Anderson Cancer Center. He is a past president of the American Society of Clinical Oncology and is one of the world’s leading authorities on breast cancer treatment. He has published more than 1,000 papers in peer-reviewed journals.

At the European Society for Medical Oncology Congress [ESMO] 2021, Dr. Hortobagyi presented overall survival results from the MONALEESA-2 trial, which compared the combination of Kisqali (which is also called ribociclib) and Femara (which is also called letrozole) to Femara alone to treat hormone-receptor-positive HER2-negative advanced-stage breast cancer in postmenopausal women.

Earlier results from the study found that adding Kisqali to Femara improved progression-free survival — the amount of time that women lived without the cancer growing. These new results found that the combination of Kisqali and Femara also improved overall survival — the
length of time women lived whether the cancer grew or not. 

Dr. Hortobagyi, welcome to the podcast.

Dr. Gabriel Hortobagyi: Thank you. Pleasure to be here.

Jamie DePolo: So, if you could, just so we all understand, could you summarize the MONALEESA-2 study for us?

Dr. Gabriel Hortobagyi: Yes. So, the MONALEESA-2 trial was designed in 2012, and it was a phase III randomized clinical trial in which 668 postmenopausal women with advanced, or metastatic, breast cancer who had not received any treatment for metastatic disease were given letrozole, and then were randomly assigned to either a placebo or ribociclib. And treatment was scheduled to be continued until evidence of tumor growth or progressive
disease was detected.

Recruitment started in early 2013 and finished in about March 2014, and we presented the first result, as you mentioned, about progression-free survival in the fall of 2016 at the ESMO Presidential Session. At that time, the results showed that the extension of disease control related to the addition of ribociclib was about 9 months — which was highly statistically significant — and more importantly, it was highly clinically relevant and significant. Many of our randomized trials that show progress and show improvement in outcomes show
improvements in progression-free survival of 2, 3, sometimes 4 months. So, 9 months in metastatic disease is a considerable leap forward. 

Now, after that analysis, we repeated the analysis a year later when additional events had occurred, and therefore the results were more mature and even more reliable. And we confirmed the exact same results with a somewhat higher level of statistical significance. And then we had to wait until sufficient events occurred to perform the overall survival analysis, which was done starting in the summer of 2021. And it was on the basis of that analysis that the presentation at ESMO was planned. And this analysis showed that the control group — the group that received letrozole plus placebo — had a median overall survival of 51 months, whereas the group that received ribociclib plus letrozole had a median survival of 63.9 months, or 64 months.

That’s a greater than 12-month prolongation of overall survival, which is wonderful news for our patients, and it is also a representation, or a reflection, of the progress made in this field. Just to put this in context: When I started in oncology in 1974, the median survival for advanced breast cancer was somewhere between 18 and 24 months. And now, with these
results, we have broken the 5-year mark, which is a considerable amount of progress. And so, we are very excited about these results.

Now, other important findings of this most recent analysis were that the side effects and toxicities we reported in 2016 had not changed. There was no new report of new or unexpected toxicity. And since more than half of the patients received ribociclib for more than 25 months — which was the median progression-free survival — that meant that the safety of this was considerable. And, in fact, some of the original patients are still receiving ribociclib at this point, almost 8 years from the onset of treatment.

In a more formal analysis, we had used validated quality-of-life instruments to assess the impact of treatment on the quality of life of our patients, and there was no detriment — or no decrease — in quality of life. And for those patients who started out with symptoms related to their cancer, there was improvement in their quality of life. So, both in terms of safety and in terms of efficacy, the results of this latest analysis were very encouraging and suggested that we have continued to make progress in this group of hormone-receptor-positive, HER2-negative breast cancers. And just to remind us that this is the most common type of breast cancer, and it represents something like 2/3 of patients with primary and metastatic breast cancer.

Jamie DePolo: Okay. Thank you for that. Now, I do want to ask: Kisqali is a CDK4/6 inhibitor and — just for everybody listening, that means it targets specific proteins that help cancer cells divide and multiply. And besides Kisqali, there are two other CDK4/6 inhibitors used to treat breast cancer, Ibrance and Verzenio. But my understanding is this study, these results that you just presented, this is the first time a CDK4/6 inhibitor has been shown to improve overall survival, is that correct?

Dr. Gabriel Hortobagyi: So, yes and no.

Jamie DePolo: Okay.

Dr. Gabriel Hortobagyi: So, there have been probably nine randomized clinical trials with one or another of these CDK4/6 inhibitors, and the initial trials were in first-line. So, the MONALEESA-2 — which is the one we were talking about today — the PALOMA-2, and the MONARCH-3 were designed for patients who had received no prior treatment for metastatic disease.

Only the MONALEESA-2 has been reported in terms of overall survival. The PALOMA-2 and the MONARCH-3 have not reported overall survival results. However, there were six other randomized trials in second- or third-line therapy — again, named PALOMA or MONALEESA or MONARCH with various numbers — and those second- or third-line trials have reported, for all three CDK4/6 inhibitors, a prolongation of progression-free survival and overall survival.

Now, the difference is that the more advanced breast cancer is, and the closer it is to a fatal outcome, the easier it is to demonstrate an overall survival benefit. And let me explain: If you think of the time that starts when a patient is diagnosed with metastatic disease, until there is a fatal outcome, patients with this type of breast cancer — but also other types of breast cancer — receive multiple types of treatment.

So, let’s say the first-line treatment works for about a year, and then the cancer starts growing again, you change to a second-line treatment. And that might work for maybe 6 months, and then the cancer starts growing again, you change to a third-line treatment and so on. And some patients receive five, six, seven, eight, sometimes 10 and more lines of therapy.

So, the contribution of any particular line of therapy is relatively modest in the context of the overall survival. So, for much of the history of clinical trials, it was much easier to show a
prolongation — a significant prolongation of disease control or what we call progression-free survival — than overall survival. And of the hundreds, or even thousands, of clinical trials we have run in breast cancer, you can count with a few fingers the number that have shown an
overall survival benefit.

So, that is the enormous significance of this particular trial, the MONALEESA-2, because it is the first time that we have shown in first-line therapy of this particular type of breast cancer that we can prolong overall survival. Now, since the other two CDK4/6 inhibitor trials have not reported, we do not know, of course, what the outcome of those will be, and we are all waiting with great interest when those trials report.

The three trials started at about the same time, although the oldest one is PALOMA-2, which started about a year before MONALEESA-2. So, we hope that these other two trials will report overall survival results within the next year or two — whether positive or negative — and, of course, that will determine where the field goes next. Because, suppose the other two trials in first-line therapy are negative and they do not show an overall survival benefit, then clearly ribociclib, or Kisqali, will be the only game in town.

On the other hand, if the other two also show an overall survival benefit of similar magnitude with similar safety results, then we will have multiple choices. And then we will have to figure out whether these three drugs are indeed interchangeable or whether one is better than
another and so on. So, that is where we stand today in terms of overall survival with the three CDK4/6 inhibitors.

Jamie DePolo: Okay. Thank you for that. That was very helpful. I do want to ask — because I know some of the people on our website, there may be a little bit of confusion, or they want to understand — why is improving overall survival versus progression-free survival so important?

Dr. Gabriel Hortobagyi: Well, most patients are interested in one of two, or both, outcomes:
length of life and quality of life. The length of life is clearly defined by what we call overall survival. The quality of life, of course, is defined by the effect the disease has on how they feel and what the treatment they receive does to how they feel.

Now, progression-free survival reflects only one relatively modest part of the overall duration of survival, whereas overall survival represents the whole duration of survival. So, because of that, it is more important to define what effect treatment has on overall survival. In the case of the MONALEESA-2 study, the progression-free survival for the ribociclib plus letrozole arm was 25 months, but the overall survival was 64 months. It’s a huge difference. And that is one
of the major reasons why we emphasize overall survival.

The other part of it is that progression-free survival is measured on the basis of tests. And sometimes, depending on when you do the test — you know, we don’t do tests every day — so if you do a test every 4 months or every 6 months, the time to progression might vary.
So, there are some technical issues there, but there are no technical issues about overall survival: you’re either alive or you’re not. And because of that, it is considered the hardest endpoint — the one that is unequivocal. But with progression-free survival, it’s a little bit more iffy. We use it because you get to progression-free survival earlier, and therefore you can make a decision about the contribution of a drug or a treatment to the overall management of that patient’s disease. But it is not the best endpoint.

Jamie DePolo: Okay. Okay. Thank you for that. Now, as you described, the MONALEESA-2
study used Kisqali in combination with Femara. But, my understanding is Kisqali can be used with any of the aromatase inhibitors. So, is it likely this improvement in overall survival will be the same no matter which aromatase inhibitor Kisqali is used with?

Dr. Gabriel Hortobagyi: So, yes. That is an important point. So, the three aromatase inhibitors
available to us today — Arimidex, letrozole, and Aromasin — are pretty much the same in terms of their efficacy. And there have been trials that have compared the three of them, and there doesn’t seem to be a clinically relevant difference in how they do. And there are no specific interactions of ribociclib — or the other two CDK4/6 inhibitors, for that matter — with these drugs.

So, I would expect that regardless of the partner we use for ribociclib, the end result will be the same. That is also true for another endocrine agent called fulvestrant, or Faslodex, which has also been combined with ribociclib, or Kisqali, in another trial. So, I think the important thing is to combine ribociclib with an endocrine partner. But all four endocrine partners that I just mentioned will have the same level of partnership with the drug, and therefore, the long-term results are expected to be the same.

Jamie DePolo: Okay. Thank you for that. That was very helpful. And, finally, so what do these results mean for a postmenopausal woman who’s been diagnosed with hormone-receptor-positive, HER2-negative, advanced-stage breast cancer? Do they change the first standard treatment for this type of breast cancer? Is that where we are now?

Dr. Gabriel Hortobagyi: So, because the second- and third-line therapy randomized trials were performed, and the duration of progression-free survival and overall survival for those second- and third-line therapies is shorter, they were reported earlier. So, for several years now there has been this controversy in the field of, “Should we add drugs like ribociclib to
endocrine therapy in first-line, or should we wait until second-line or third-line? Will that make a difference?”

And the reasons for that controversy were related in part to cost. These drugs cost upwards of $100,000 per year. And, in part, because every time you combine two drugs, you increase the chances of having some side effects or toxicities. And there were some smart calculations as to, “Well, if you do it in first-line, then you get a longer progression-free survival, but if you do it in second-line, you might just get the same overall survival with a shorter progression-free survival and lower cost,” and so on and so forth. But now with this hard endpoint reached, and having broken the 5-year margin, if you wish, there is not much question that this is what we should do up front: use the best treatment, the most effective treatment, up front. 

And, therefore, this should be the standard for every postmenopausal patient with advanced, hormone-receptor-positive breast cancer, unless there is some specific contraindication to this drug — and there are very few. So, I would imagine that the great majority of patients should be treated with this combination.

Jamie DePolo: Dr. Hortobagyi, thank you so much for your insights. This has been really helpful.

Dr. Gabriel Hortobagyi: My pleasure.