MONALEESA Data in HR+/HER2- MBC: Sequencing Therapy

Insight on how to best sequence therapy for patients with HR+/HER2- advanced breast cancer based on updated data from the MONALEESA trials.

Joyce O’Shaughnessy, MD: We have survival with letrozole with ribociclib with the postmenopausal women in MONALEESA-2. In MONALEESA-7, we have a robust survival advantage in premenopausal patients. It’s indicated with the nonsteroidal AI [aromatase inhibitor], plus an LHRH [luteinizing hormone-releasing hormone] agonist, plus ribociclib. It also leads to improved survival in the premenopausal population. Then we have the first- and second-line trial, the MONALEESA-3, which is fulvestrant with or without ribociclib. Put them together, and you’ve got another survival advantage. You’ve got letrozole and fulvestrant, premenopausal and postmenopausal, in the first and second lines. It’s a robust portfolio emerging in terms of survival advantages with the MONALEESA series, and it’s very impressive. If someone had an aromatase inhibitor awhile back and had a treatment-free interval off the aromatase inhibitor, let’s say for a few years, or was AI-naïve, do you ever utilize the fulvestrant-ribociclib data from MONALEESA-3? Or would you go with the letrozole and ribociclib? Do we have a reason to pick 1 over the other? What do you think, Neil?

Neil Iyengar, MD: That’s a great question, Joyce. That’s where having all the information up front helps with some of these decisions. Certainly, in the case that you described, where perhaps the patient has been previously exposed to an aromatase inhibitor but has had a disease-free interval, that might suggest that endocrine resistance isn’t playing a role. So I’d be inclined to use the AI again in the first-line setting. What would help with that decision-making are molecular data. If we know, for example, that an individual harbors a PI3 kinase mutation in the tumor, and we’re going to reach to alpelisib in the second line, then that’s additional rationale for me to save fulvestrant to partner with alpelisib in the second line. In contrast, if we know from either the natural history or the molecular data that somebody is endocrine therapy-resistant or harbors an ESR1 mutation, then I’ll likely use fulvestrant up front. That’s how I think about it, and our thinking on this will likely evolve as we see newer and additional endocrine therapy partners come down the pipeline.

Joyce O’Shaughnessy, MD: Thanks, Neil. How about Gabe? Some people don’t tolerate AIs. They just couldn’t take them in the curative setting. It’s nice to have an alternative. It’s nice to have a survival advantage in the first-line setting with fulvestrant. Any other thoughts on that?

Gabriel Hortobagyi, MD, MACP, FASCO: I think of this in 2 ways. One is that in the MONALEESA-2, you could have had an AI before, as long as you had had an AI-free interval of greater than 12 months. There are no data to suggest that those patients did any worse, but this reminds me a lot of the way we think about anti–HER2 [human epidermal growth factor receptor 2] therapy. We had heated discussions about what chemotherapy backbone we should use. Now we’re pretty much convinced that the AI therapy makes a difference regardless of the chemotherapy partner. The same thing happens here. The CDK4/6 inhibitor has such a powerful effect that whether you use an AI or fulvestrant makes relatively little difference. Remember that in a randomized trial, fulvestrant was superior to anastrozole. These data suggest that it makes no difference because it’s the combination, and largely the CDK4/6 inhibitor, that has the impact.

Joyce O’Shaughnessy, MD: That’s a good analogy. I like that. That made things true to me too.

Transcript edited for clarity.

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