MONALEESA-3: Updated Survival

Nicholas McAndrew, MD, MSCE: I’m Nick McAndrew. I’m a medical oncologist at UCLA [University of California, Los Angeles]. I’m a health scientist assistant and a clinical professor of medicine. It’s a pleasure to be here to talk about some ASCO [American Society of Clinical Oncology Annual Meeting] updates.

When thinking about some of the updated overall survival data that were recently presented at the 2021 ASCO Annual Meeting for MONALEESA-3, and where this fits into the overall pool of data for CDK4/6 inhibitors, it’s important to go back and think about some of the prior background of CDK4/6 inhibitors. Of course, these molecules were first noted to be active in hormone receptor–positive, HER2 [human epidermal growth factor receptor 2]–negative breast cancer. Some of the early studies by our group at UCLA showed that when tested against cell lines of lots of tumor subtypes, including different breast cancer subtypes, the CDK4/6 inhibitors seemed to be extremely effective at inhibiting growth in the hormone receptor–positive, HER2- cell lines compared with other breast cancer subtypes.

This and other preclinical studies led to a variety of phase 3 trials looking at numerous compounds within this group; first the PALOMA studies, with PALOMA-2 being a first-line study and PALOMA-3 being a second-line study in the metastatic setting with fulvestrant and palbociclib. MONALEESA-3 is a phase 3 study in the endocrine-resistant population and also the endocrine-sensitive in first-line population, which is a unique aspect, with fulvestrant and ribociclib. There was also MONARCH 2, with abemaciclib and fulvestrant.

The initial reporting on these studies first reported the progression-free survival data in this population. These drugs gained approval based on improved progression-free survival data, which were all very similar when it was first announced. However, since the overall survival data have come out with these compounds, we’ve seen somewhat of a difference between the overall survival end point as compared among the 3 trials. It’s always difficult to compare trials, but it’s notable that when the overall survival outcomes were initially reported previously in MONALEESA-3 and MONARCH-2, they were noted to be positive with improved overall survival benefit. However, with PALOMA-3, the initial overall survival reporting showed that it did not meet its survival end point.

More recently, the updated MONALEESA-3 overall survival data were presented, which was an exploratory overall survival analysis with longer progression-free survival follow-up. These were patients who were either men or postmenopausal women who had received less than or equal to 1 prior line of endocrine therapy for advanced hormone receptor–positive, HER2- breast cancer. Patients were randomized to receive fulvestrant or ribociclib. About half the patients in the study were in the first-line setting, so these were patients who had never seen any systemic therapy for their metastatic breast cancer, which is an important component to keep in mind. The other studies included primarily patients with endocrine-resistant disease or disease that had progressed after 1 line of endocrine therapy.

Previous progression-free survival and overall survival analyses were positive. At this longer survival follow-up with over 56 months of median follow-up, there continued to be an over-1-year benefit in overall survival with fulvestrant and ribociclib as compared with fulvestrant alone. Looking at the landmark analysis, there was a 15% absolute improvement in overall survival at 46% vs around 31% for the fulvestrant group. When breaking this apart by patients who had done first-line therapy vs patients who had received this combination in the second line, we saw very similar results in terms of overall survival. There was still overall survival benefit in both these lines. Of course, the numbers were much smaller, so this is an exploratory analysis. Similarly, in the endocrine-sensitive vs endocrine-resistant groups, it was still numerically longer median overall survival, even in the endocrine-resistant population. Although with this subgroup, it becomes difficult to see statistical significance. Of course, this is an exploratory analysis.

They also looked at a host of other end points that are clinically important, including time to chemotherapy; chemotherapy-free survival, which is an important quality-of-life metric; and progression-free survival 2, meaning the amount of time patients were on the next line of therapy before they progressed after ribociclib. All these outcomes were improved with the addition of ribociclib. This was an important secondary analysis that showed us even longer follow-up and longer secondary outcomes that help us understand that, even in the first-line setting, adding a CDK4/6 inhibitor—in this case ribociclib—has a positive impact on a host of very important outcomes.

It’s hard to find a patient who, for purely medical reasons, would not be appropriate for a CDK4/6 inhibitor. Because there are numerous that are approved, I tend to go by adverse effects, convenience, as well as data. Ribociclib and abemaciclib have very clear and convincing overall survival benefits, as noted by the primary analysis for their studies. Whereas PALOMA-3, at its original preplanned analysis, didn’t show improved overall survival. Though at a subsequent exploratory analysis, there was some suggestion of overall survival benefit.

That being said, I tend to use ribociclib. All other things potentially being equal, I find that it’s easy to dose reduce patients with ribociclib because it comes in 200-mg capsules. From a very crude cost-benefit analysis that our institution performed, because it doesn’t require a secondary co-pay to dose reduce patients—a lot of patients need to be dose reduced in the first cycle because of neutropenia—we found that it’s much more cost-effective to start with ribociclib and instruct the patient to take 1 less pill halfway through the cycle, rather than prescribing a different dose and having a second co-pay.

Transcript edited for clarity.