MONALEESA-2 and MONALEESA-3: Frontline Ribociclib + Endocrine Therapy


Highlights from the MONALEESA-2 and -3 trials combining frontline ribociclib with endocrine therapy in patients with HR+/HER2- metastatic breast cancer.


Richard Finn, MD: Ribociclib is a novel CDK4/6 inhibitor that, like the others, has been shown to improve progression-free survival in advanced hormone receptor-positive HER2-negative breast cancer. This drug is dosed 3 weeks on and 1 week off. From its pivotal studies, we've seen that it is generally well-tolerated. Like other CDK4/6 inhibitors it has a class effect—it does cause some bone marrow suppression, mostly leukopenia and neutropenia—but the incidence of neutropenic fever is relatively uncommon. There are also some guidelines to do ECG [electrocardiogram] monitoring at the beginning of treatment with ribociclib, only to monitor for some QTC prolongation that can occur, and in that regard, to be cognizant of other drugs a patient might be on that can prolong the QTC. However, with that being said, this drug is very well tolerated and is broadly used in this space, and that is supported by several phase 3 studies.

MONALEESA-2 was a study that looked at ribociclib in combination with an aromatase inhibitor, either letrozole or anastrozole, and interestingly, MONALEESA-3 was generally looking at a population of patients who had not had a prior CDK inhibitor and who had progressed on an AI [aromatase inhibitor], and that was in combination with fulvestrant. The comparator studies with the other compounds would be PALOMA-3 or MONARCH-2 with palbociclib and abemaciclib respectively. Uniquely in MONALEESA-3, they also had a frontline population. This was a population that got ribociclib and fulvestrant in the frontline setting. Now there's been a lot of interest in using endocrine treatment in the frontline setting even if we go back historically before the introduction of CDK inhibitors. However, studies looking at AIs versus fulvestrant really did not show a significant improvement in outcomes in the general population with the use of fulvestrant. Given that it's intramuscular, a lot of us and patients tend to prefer an oral regimen in that setting. However, we now see that both an AI and ribociclib as well as fulvestrant and ribociclib are yielding significant improvements in overall survival.

These were secondary end points in these studies, and they are very convincing that the use of CDK4/6 inhibitors is pivotal in our patients with ER+ HER2-negative breast cancer. When we look at the subgroups from these studies, we're not able to identify a group that does not get a benefit from the addition of a CDK inhibitor to AI or fulvestrant. When we look at several clinical subgroups such as disease-free interval performance status, age, visceral versus nonvisceral disease, or bone-only disease, there are very consistent benefits. We have not been able to really identify a clinical group of patients that does not benefit from this class. Also, we've been looking for biomarkers, and there have been some molecular profiling studies done from the MONALEESA studies, looking at molecular subtypes of breast cancer such as the luminal A, luminal B, and HER2-enriched. Keep in mind, clinically, when we assess these patients in practice, we're just using estrogen receptor, progesterone receptor, and HER2. However, we do know that there are distinct molecular subtypes that have different prognoses, but they are not necessarily predictive of response. What I mean by that is that regardless of the subtype of breast cancer based on molecular profiling, there's still a consistent benefit to the addition of a CDK inhibitor to endocrine treatment. That we have seen in the recent data coming out of the MONALEESA studies, as well as with the studies with palbociclib and abemaciclib as well.

Transcript edited for clarity.

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