Ribociclib Results Hailed as Practice Changing in HR+ Breast Cancer

Gabriel N. Hortobagyi, MD

An interim analysis of data from the randomized, double-blind MONALEESA-2 trial has shown that the addition of the CDK4/6 inhibitor ribociclib to letrozole significantly improved progression-free survival (PFS) in postmenopausal women with hormone receptor (HR)­—positive advanced breast cancer.

Patients in the ribociclib arm had a 44% reduction in the risk of progression or death compared with patients who placebo plus received hormone therapy (HR, 0.556; 95% CI, 0.43-0.72; P = .00000329). This difference satisfied prespecified statistical requirements for superiority.

“It is clear that these are practice-changing findings,” said Gabriel N. Hortobagyi, MD. “Going forward, the treatment of choice for these same postmenopausal women with HR-positive breast cancer, will be a combination of a drug like letrozole with a CDK4/6 inhibitor such as ribociclib.”

In an interview with OncLive, Hortobagyi, professor of Medicine at the University of Texas MD Anderson Cancer Center, discusses the design of the MONALEESA-2 trial, the impact that these findings stand to have in this setting, and the integral role of hormonal therapy in the treatment of patients with HR-positive breast cancer.

OncLive: Could you provide an overview of the MONALEESA-2 trial?

Hortobagyi: The MONALEESA-2 trial was designed as a phase III randomized placebo-controlled trial for postmenopausal women with HR-positive metastatic breast cancer who had not received prior treatment for advanced disease. The study recruited 668 patients from about 29 countries, 223 centers.

After stratifying them by the presence or absence of liver or lung metastases, patients were randomized in a 1:1 ratio to receive either letrozole plus ribociclib or letrozole plus placebo. Letrozole was administered daily at the standard dose of 2.5 mg daily, while ribociclib was administered at 600 mg daily for 21 days in a row followed by a 1-week interruption. Treatment was continued until disease got worse or progression.

The primary efficacy variable was progression-free survival. The study was designed so that, every 8 weeks, we repeated the staging workup to determine whether the disease was stable, responding, or had progressed. That was done for the first 18 months of the study, and after that, it was done somewhat less frequently. But the data I’m talking about today really focused on the first 15 months or so, because the median follow-up at the time of this analysis, which is based on data up until January 29, 2016, was a follow-up of 15.3 months.

At the time of that analysis, which was an interim analysis by the way, and interim analyses are designed to reject a study because of futility, which was not the case, or because we want to determine a favorable therapeutic effect early, which was the case here. So under normal circumstances, you wait until a definitive analysis to determine whether the treatment is good or not. In this case, well before that, with only about 70% of the expected PFS events, we found such a significant difference between the 2 treatment arms that the study was declared as having reached its primary efficacy variable.

So, at that time, the 2 treatments were so different that the hazard ratio showed a 44% reduction in PFS events, with a highly significant P value, and with curves that started to diverge at the first evaluation at 8 weeks, and continued to diverge as time went on.

So this is a very stable and powerful observation that exceeds the power of the study as designed. Because of that, we reached our objective several months earlier than we had planned, which is a wonderful surprise when running a clinical trial.

What is the significance of these results in the general treatment landscape of HR-positive breast cancer?

Up until the development of the CDK4/6 inhibitors, the standard of care for managing patients with HR-positive metastatic breast cancer was an aromatase inhibitor such as letrozole or anastrozole. Since the development of these very favorable results, it is clear that these are practice-changing findings. And, going forward, the treatment of choice for these same postmenopausal women with HR-positive breast cancer will be a combination of a drug like letrozole with a CDK4/6 inhibitor such as ribociclib.

And that’s a major change, because with letrozole alone, the best data—which incidentally come from the MONALEESA-2 trial—is about a 14-month PFS. And with the addition of ribociclib, we are adding a significant number of months, to be determined by more mature data from the MONALEESA-2 trial. And that is likely to impact the overall survival of these patients, though we still await a more mature analysis of this study.

Are there plans to combine ribociclib with other agents in the future?

Clearly, there are a number of other hormonal agents. The MONALEESA-7 trial, for instance, is a study that will focus on premenopausal, younger women. And for younger women, the different hormonal agents being used include tamoxifen and goserelin, as well as a combination of goserelin with an aromatase inhibitor. So ribociclib is being combined with all of those, individually or in combination, and it is important to establish that this is not only an improvement in the effect of letrozole, but all types of hormonal therapy.

So you’ll hear of other studies at this meeting that there’s another very important hormonal agent called fulvestrant, and we hope to also look at fulvestrant in combination with other agents. Fulvestrant, at this point, based on the most recent data, seems to be the most effective hormonal agent. My expectation would be that adding ribociclib to that would also result in significant improvement.

And then there are other types of breast cancer, different from HR-positive breast cancer, where we have had a preliminary look at preclinical models, where CDK4/6 inhibitors are very likely to improve the effectiveness of standard therapy. And those studies are either in early stages/in progress, so I can’t comment on them, but my expectations are that, what we observed in MONALEESA-2 is just the stepping stone for moving forward with this agent and for expanding its indications.

Ultimately, of course, the major effect of a drug like ribociclib will be in the adjuvant setting. We have plans to develop a clinical trial looking at the three-quarters of women with primary breast cancer who have HR-positive breast cancer. So that’s where this is all heading. The results of MONALEESA-2 are an extremely important foundation upon which to develop these further studies.

Perhaps I should mention that the CDK4/6 inhibitors are not only being combined with endocrine therapy, but other targeted agents as well that we’re looking at. For instance, a predecessor of the MONALEESA-2 trial was the BOLERO-2 trial, in which we combined endocrine therapy with an mTOR inhibitor called everolimus (Afinitor). So we have trials in which we take that platform and add ribociclib as a third drug, and those studies are ongoing, and we hope that the triplet will be more effective than either doublet. So there’s much more activity than a brief presentation at this congress allows one to expand upon, but there’s a lot of excitement about this field and all the possibilities.

What would you like the community oncologist to take away from your presentation?

I think there are 3 main messages. First, it is clear that hormonal therapy continues to be the most important component of the treatment of HR-positive metastatic breast cancer. Second, there is progress being made in hormone-dependent metastatic breast cancer. We’re not just stuck with aromatase inhibitors from 20 years ago. And finally, these results are truly practice changing. As soon as this agent is approved by the appropriate regulatory agencies, I think it should be the treatment of choice.

What do you hope to see in this treatment landscape in the next 5 to 10 years?

I would hope that these results would expand to other subsets of HR-positive breast cancer in first-, second- and perhaps further lines of therapy. I hope they will expand to both older and younger women. As I mentioned, in the adjuvant setting, 5 years from now, we’ll be close to maturity, and certainly having completed accrual and all of that. Ultimately, I predict that the addition of CDK4/6 inhibitors will result in an improvement not only in PFS but overall survival in metastatic disease, and perhaps increase the relapse-free survival of primary breast cancer.

Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.