Hortobagyi Discusses MONALEESA-2 and the Importance of Overall Survival in Breast Cancer Care

Gabriel N. Hortobagyi, MD, is a professor of medicine, Department of Breast Medical Oncology, in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston, Texas. In 2019, when he received a major award from the American Society of Clinical Oncology (ASCO), he noted that during his career of more than 40 years, he had witnessed improvement in breast cancer treatment that had reduced the mortality rate by 40% and improved the quality of life for patients. Hortobagyi has been at cutting edge of one of the more important developments of recent years—the arrival of CDK4/6 inhibitors. He developed, implemented, and chaired the MONALEESA-2 phase 3 trial, which evaluated the safety and efficacy of ribociclib (Kisqali) in combination with letrozole in patients with hormone receptor–positive metastatic breast cancer.¹

Recently, Hortobagyi spoke with The American Journal of Managed Care® (AJMC®) about the importance of the overall survival results in the MONALEESA-2 trial and where CDK4/6 inhibitors fit in the breast cancer armamentarium.

AJMC®: From a historical perspective, what have outcomes looked like for patients who have hormone receptor–positive, HER2-negative breast cancer?

Hortobagyi: Historically, when one goes back to the 1970s, before the estrogen receptor became a standard test, the median survival for patients with metastatic breast cancer was between 18 and 24 months. Once we identify the hormone receptor–positive breast cancer population, let's move forward about 15 to 20 years. But it became apparent that with existing therapy, the median survival for the same population was somewhere between 2 and 2.5 years. And then we have to fast forward until today, when we have—for the first time—crossed the 5-year barrier with recently presented data. So there has been significant progress, both in terms of the results of clinical trials, and in terms of the application of emerging knowledge and emerging therapeutics.

AJMC®: Can you expand on the survival rates you mentioned in this population? What are the 5-year survival rates for this subset of breast cancer? And how does this compare to other types of breast cancer?

Hortobagyi: Today, we recognize about 4 different clinical and molecular subtypes of breast cancer. The molecular and clinical subtypes are largely overlapping, but not completely overlapping. And the best population-based information is derived from clinical subtypes, which are defined by the expression of the estrogen receptor, progesterone receptor, and HER2 or the lack thereof. If you look at the best prognostic category today, it is the hormone receptor–positive, HER2-negative breast cancer. And the best clinical trial results show a median survival in the metastatic setting of greater than 5 years. Population-based data, which [likely] would be behind the clinical trial scenario, would suggest somewhere between 3.5 and 4.5 [years] for the HER2-positive subtype. This used to be the worst prognostic category with a median survival of about 18 months, which preceded the development of anti-HER2 therapy. Now, the best clinical trial results suggest that the median survival is around 15 months. And although population-based results, which include all kinds of other issues, do not quite get there, [they are] somewhere around 3 to 3.5 years.

The worst prognostic population is what we call the triple-negative breast cancer group, or the group that harbors breast cancers that do not express either hormone receptors or HER2. In that group, despite marked investment in effort, resources, and research, the median survival remained somewhere around a year and a half. In some recent clinical trials, it has gotten up to maybe 2 years, 24 months, maybe a couple months longer than that, but it remains a straggler.

So, among all of the breast cancers in the metastatic setting, triple-negative breast cancer has the worst prognosis today. There is a marked unmet need in that group.

AJMC®: You recently presented MONALEESA-2 trial data at the European Society of Medical Oncology (ESMO) 2021 meeting.² Can you tell us a little bit more about this trial? How was it designed and what particular population was being studied?

Hortobagyi: For a number of years, there has been interest in targeting the cell cycle, because the cell cycle has a prominent role in cancers or malignant diseases in general, and breast cancer and certain types of breast cancer in particular. So, there have been attempts since the mid-1990s to target 2 components of the cell cycle, and those have largely failed, because the agents being tested were not very selective—and were associated with significant toxicity. Then, [in the years after 2010] the second- or third-generation more specific CDK4/6 inhibitors appeared. Very close to each other, 3 separate pharmaceutical companies came up with 3 somewhat similar CDK4/6 inhibitors, even though there are some subtle differences in pharmacokinetics and targeting and whatnot. So, the MONALEESA-2 trial was designed shortly after the completion of the phase 1 study in 2012. With the support of its pharmaceutical sponsor, we designed a phase 3 trial in metastatic breast cancer. And because the best data were obtained in hormone receptor–positive, HER2-negative cell lines, we targeted that population. And of course, we targeted the metastatic setting. It was a randomized, prospective, double-blind, placebo-controlled trial for postmenopausal women with hormone receptor–positive HER2-negative breast cancer, who had not had any treatment for metastatic disease, and who had completed adjuvant endocrine therapy, if any, at least 12 months before the initiation of protocol therapy.

The public trial was designed as a 1:1 randomization. And everybody received the letrozole at the standard 2.5 mg daily continuously. And half of the patients after stratification were assigned to either ribociclib 600 mg daily, days 1 to 21 with a 1-week break, or placebo in the same schedule. The development of this trial proceeded very rapidly. There was a lot of enthusiasm from the concept on a proverbial cocktail napkin until implementation—only about 10 to 11 months elapsed. So, in early 2013, we initiated accrual; we completed accrual 14 months later. About 600 patients were recruited. And upon initiation, we noticed that treatment was well tolerated. So, we continued as designed until either progression or intolerable toxicity, which was a rare event. So that was the design of this clinical trial.

AJMC®:As you mentioned, this trial involved postmenopausal women with breast cancer. Can you tell us just very briefly, what is the difference in treating a patient with hormone receptor–positive HER2-negative breast cancer who is postmenopausal as opposed to someone who is perimenopausal or premenopausal?

Hortobagyi: Before the development of combination endocrine therapies, the standard of care for managing this type of breast cancer was single-agent endocrine therapy, with tamoxifen and aromatase inhibitors being the leading choices. Now, postmenopausal women represent about three-quarters of [the patients with] hormone receptor–positive HER2-negative breast cancer, with premenopausal women being, of course, one-quarter. And because of that preponderance, most of the clinical trials for this population were designed for postmenopausal women. The additional reason for this was that drugs such as the aromatase inhibitors don’t seem to work in premenopausal women; the production of endogenous estrogens by the ovaries was too prominent and too effective to be overcome by inhibition of aromatase. So, the predominant interventions for premenopausal women were either ablation or suppression of ovarian function, with either surgical oophorectomy radiation ablation, or the use of chemical suppressants such as [luteinizing hormone-releasing hormone] agonists.

That was the story, until we came to the group of combination endocrine therapies. That has changed to a large extent today, because it has been recognized that the chemical suppression of ovarian function is quite effective with the overwhelming majority of premenopausal women, and the only remaining difference between postmenopausal and premenopausal women. When utilizing optimal therapy, the most effective endocrine therapy is to add ovarian function suppression to premenopausal women. Now, that sounds very easy and very straightforward. But it took about a couple of decades to come to that consensus in our field. Today, when we develop a treatment for postmenopausal women, which continues to be the predominant direction, we tend to extrapolate to premenopausal women by adding ovarian function suppression now in the context of ribociblib and MONALEESA-2, and to give credit to the sponsor of this agent, there was a specific clinical trial that was developed for premenopausal women with hormone receptor–positive HER2-negative metastatic breast cancer that was just as successful as the MONALEESA-2. And we'll come back to the sets of randomized clinical trials with ribociclib later on.

AJMC®:Getting back to the MONALEESA-2 trial. Tell us a little bit more about the safety and efficacy results—what were some of the key takeaways that payers and clinicians should know about this study?

Hortobagyi: I mentioned that MONALEESA-2 completed accrual in early 2014, and then we needed to let it mature. In the summer of 2016, we reached the sufficient number of events for analysis, which was an interim analysis at that time. But the differences were so prominent that the data monitoring committee recommended release of data. So those were presented at the ESMO meeting and showed that with a follow-up of about 2 years, the ribociclib arm has outperformed the control arm by essentially doubling the median event-free survival or progression-free survival (PFS) even though in the ribociclib arm at that time, the median PFS had not been reached, but it was estimated judging by the Kaplan-Meier curve that it would far exceed the performance of the letrozole-plus-placebo arm.

So, it was an exciting event; it was very well received by the community. On the basis of those results I should say the regulatory agencies approved the use of ribociclib in combination with letrozole or an aromatase inhibitor in general for widespread utilization in this group of patients. Now fast forward 5 years because of course, while the study was powered for both PFS and overall survival, you need a sufficient number of events in order for this study to mature. At the time of the PFS analysis, which I repeat was an interim analysis, there were insufficient overall survival events to lead to an overall survival analysis.

Now in 2021, we reached the threshold of events that allowed the definitive overall survival analysis. And the overall survival analysis, which was again presented at the ESMO meeting, because of the timing issues show the highly significant prolongation of overall survival, with the control group having a median overall survival of about 51 months, and the ribociclib arm showing an overall survival of about 63 months and change. So, [this was] a prolongation of overall survival at the median level of more than a year. This was very, very exciting because it was really the first time that we had demonstrated in a phase 3 trial of hormone receptor–positive breast cancer such a significant clinically relevant prolongation in overall survival. In most of our clinical trials, in any type of breast cancer until very recently, when there was an overall survival benefit, which was only in a minority of clinical trials…the benefit was numerically in the 2 to 4 month range. To see a survival benefit in the more than 1-year range, that was extraordinarily positive, and, of course, very encouraging. That was the result in terms of the therapeutic outcomes. Now, the median overall survival does not reflect the entirety of the benefit of the intervention. It is also important to understand that within a median follow-up that now approaches or exceeds 6.5 years, the differences between the survival curves continue to expand. For years, we had a difference of roughly 4.5% between the 2 curves. At 5 years, that difference expanded to about 8%. And at 6 years that difference reached 12%. These are absolute percentage differences. It was very encouraging to see that because this reflects the long-term benefit derived from the introduction of this combination into the management of these patients.

Now, all of this benefit, of course, comes at the price. Whenever you put 2 drugs together, you're likely to see more side effects than if you use a single drug. But it was encouraging to see with the overall survival results of the MONALEESA-2 trial, that first of all, with 5 years of additional follow-up there were no new safety signals. The same side effects we had reported in 2016 were the same side effects. There were no cumulative toxicities; there was no lethal toxicity. And while there were some side effects, reassuringly, [these were] the same qualitatively and quantitatively as those reported earlier.

Now, what are those side effects? It is important that when you report on the adverse events in a clinical trial, you report anything and everything that could be related could be related or might be related to the administration of that drug. And some of those are symptomatic, some of those are laboratory….With the addition of ribociclib to letrozole is a series of hematologic suppression, so leukopenia, neutropenia, secondary anemia, and thrombocytopenia. In most cases, those are grade 1 or 2, although in a small percentage of patients, they reach a grade 3 or 4, there were no grade 5 toxicities. The incidence of leukopenia [and] neutropenia was lower than what you see with chemotherapy, but it was clearly there.

Now the fear with leukopenia [and] neutropenia is that lowering the host defenses, it will increase the incidence of infectious complications, and specifically neutropenic fever. The incidence of neutropenic fever in this study was about 3%. So, it was very low. And that reassured us. Even after 6.5 years of therapy, there was no increase. There was no cumulative toxicity. So, this is mostly a laboratory finding without a clinical consequence. There were some other side effects that were mostly in the grade 1 to 2 category, such as fatigue, some nausea, some diarrhea, and a couple of very small frequency findings. One was another laboratory finding, which was prolongation of the QT interval, which was present in about 3.5% of the patients treated with the arrival cycle, interestingly, also in about 1.5% of patients being with placebo. So, it's not the entire figure, but just the difference. And it is, again, a laboratory finding without clinical consequence. And the other one, which is a class effect of CDK4/6 inhibitors, which is noninfectious pneumonitis, which happens in a very small percentage of patients. It’s largely reversible with interruption or discontinuation of therapy. So overall, this was very well tolerated. The proof is that some patients, 6.5 years later, are still receiving ribociclib and are still tolerating it well and continue treatment with a high quality of life.

AJMC®:What are the implications of this trial are on the treatment of hormone receptor–positive HER2-negative breast cancer? In particular, how will these overall survival results impact treatment selection moving forward?

Hortobagyi: First, these results are not presented in isolation. But the MONALEESA-2 trial results were followed by the MONALEESA-3 and then the MONALEESA-7, designed specifically for premenopausal women as I mentioned earlier, and the MONALEESA-3 for a combined group of first-line and second- line patients. In all 3 of them now have shown a significant prolongation of PFS and a significant prolongation of overall survival. Now, MONALEESA-2 was the oldest study and the first to be started, but the others—because they look at different populations—reported earlier because the median PFS and median overall survival is shorter in those trials.

But now, we see that the addition of ribociclib to letrozole provides a significant and clinically relevant improvement in or high quality in overall survival to patients with hormone receptor–positive HER2-negative breast cancer, regardless of the endocrine partners, since it happens both with fulvestrant and aromatase inhibitor regardless of menopausal status and regardless of line of therapy. Those were compelling results, when the PFS results of these trials and those of the other CDK4/6 inhibitors became available [several years ago]. Then there was discussion about what to do with these data. Should everybody with these stages of disease receive automatically a CDK4/6 inhibitor in combination with endocrine therapy, or should we wait until maybe we could get the same bang for the buck without spending as much money and then exposing the patients with the combination related side effects? With these overall survival data, I think that discussion is pretty much put to rest. A 1-year prolongation of overall survival is not something that you can achieve if you wait until second-line or third-line. I think it is compelling. With the exception of those very few patients who, for whatever reasons, cannot receive a combination with ribociclib or those who have some contraindication to combination therapy, I think the great majority of patients with hormone receptor–positive HER2-negative metastatic breast cancer should receive combination therapy with ribociclib today. And I emphasize ribociclib, because this is the only CDK4/6 inhibitor at this time, that has shown a prolongation in overall survival in all aspects of metastatic disease.

We are still awaiting the results of phase 3 trials in first-line therapy with the other CDK4/6 inhibitors, palbociclib and abemaciclib, and will, of course, need to absorb those results when they become available and determine what those results would suggest, but until such a date those results become available I think these are the best results in clinical trials and should be applied to the population in preference to other combinations.

AJMC®:What are you personally looking forward to that’s on the horizon?

Hortobagyi: You know, it reminds me a little bit of when, several decades ago, we got the new third- generation selective aromatase inhibitors. And some expert mentioned that there was going to be no more progress in this field because everything had been discovered. And of course, famous last words, because there is much excitement about what's going on. So, what am I excited about? Well, I'm excited about a variety of things in this field. Number one, we are developing a much greater and much more in-depth understanding of the mechanisms of resistance to CDK4/6 inhibitors. And, of course, the various clinical trials with these agents have dedicated a substantial amount of effort and resources to understand that—because at the end of the day, and as far as we can tell, the great majority of patients who receive these drugs will eventually develop resistance to them. Hopefully, some of them will not, but we will only know that in another 5 or 10 years. Understanding the mechanisms of resistance will lead us, and this is leading to the development of strategies to reverse resistance or to prevent the development of resistance. And I think that is a critically important and very exciting field.

Another very important and exciting field is the development of other endocrine agents. And prominent among them is the development of oral selective estrogen receptor downregulators or degraders (SERD). And just over the past couple of days, we heard the results of a very exciting randomized trial with one of them that showed a significant benefit of that agent over the only existing and approved SERD which is for fulvestrant. Now, these agents are exciting because, first, they will allow us to explore the full dose range with these agents and, second, because they are equally or even more effective in those tumors that have ESR1 mutations, which represents one mechanism of resistance, at least 2 aromatase inhibitors, so that's very exciting.

Then, as part of the overcoming resistance to endocrine therapy in general, is the development of a number of other agents: mTOR inhibitors, P13 kinase inhibitors, AKT inhibitors, MEK inhibitors and so on. There is a plethora of these agents and concepts coming down the pike. Also, [I recently] heard a very exciting presentation, which deals with resistance to CDK4/6 inhibitors—and CDK4/6 are just a part of the entire cell cycle mechanism. This particular paper was about a new experimental agent that focuses on CDK7—and dysregulation of CDK7 appears to be one of the mechanisms of resistance to CDK5/6 inhibitors—and this agent showed the affinity of activity and good tolerance in a small clinical trial. But having said that, there is much emphasis and interest in developing other CDK inhibitors focusing on CDK2, CDK7, CDK9, perhaps. So, there's a lot of excitement in this field. And then there's, of course, the better understanding of which of these patients will—and which of them will not—benefit from chemotherapy. We know now that in the primary setting, we can spare about half of patients with hormone receptor–positive HER2-negative breast cancer from the side effects of chemotherapy because they won’t benefit from it. So, there's no point in exposing them to that. And that will also open up the door for additional exploration of novel concepts and new ideas in in this field.

AJMC®:Are there any closing considerations around breast cancer that you'd like to discuss for our audience?

Hortobagyi: So, I have been in this field for 45 years now. And when I started, we had for the entire field of oncology, somewhere between 8 and 10 FDA-approved drugs. Today, we have well over 400. And more importantly, the understanding we have acquired over these past several decades is just amazing. And this increased understanding and increased knowledge will certainly lead to additional improvements in what we do, in treatment and diagnosis and in prevention of the disease. I'm very, very excited because of that. As tangible proof of that, as discussed earlier, [we’ve gone from] from a median survival of about 18 to 24 months [to] median survival that exceeds 5 years in the majority of patients with breast cancer. In another subset, HER2-positive breast cancer, we are approaching 5 years. So that is a huge improvement. Granted, more is needed, but it's a huge improvement. And while we didn't talk much about progress in the triple-negative breast cancer group, the introduction of immune checkpoint inhibitors seems to be making an important difference in that group. As that field develops further and is refined, and is combined with other targeted therapeutics, I think we will see similar improvement in the outcomes of those patients. There’s much reason to be excited and optimistic about this field.

References

1. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer Ann Oncol. 2019;30(11):1842. doi:10.1093/annonc/mdz215
2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival (OS) results from the phase II MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32(suppl 5) S1283-S1346. doi:10.1016/annonc/annonc741

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