Hope S. Rugo, MD: MONARCH-2, recently presented and published, is a very interesting study that although it looks similar to PALOMA-3 and will look similar to MONALEESA-3 when it’s presented is actually quite different. This trial randomized patients who were postmenopausal with metastatic hormone receptor-positive breast cancer who had progressed on one endocrine therapy in the metastatic setting to receive fulvestrant with either abemaciclib given continuously for all the time or fulvestrant with a placebo. The real differences in this trial, besides the CDK4/6 inhibitor, is the patient eligibility. So, you couldn’t have received 2 lines of hormone therapy, regardless of what those hormonal agents were in the metastatic setting.

And if you’d relapse on adjuvant hormone therapy or shortly after completing adjuvant hormone therapy, you also needed to go on the fulvestrant treatment with the MONARCH trial treatment as well in the first-line metastatic setting. You couldn’t get a hormone agent and then go on to MONARCH-2. So, that was different. And also, you couldn’t receive any chemotherapy for metastatic breast cancer. This group of patients were much less heavily pretreated than the patients in PALOMA-3 and who will be less heavily pretreated than MONALEESA-3.

The reasons for this, of course, is they wanted to have their best shot at approval being the third kid on the block, and they wanted to look at a patient population who had very hormone-responsive disease. And, in fact, they did. Actually, the defined a group of patients who had very hormone-responsive breast cancer. So, their actually progression-free survival in the just fulvestrant and placebo arm is longer than that seen in any other fulvestrant trial, because they picked a group of patients who were more like the patients who were treated on the FALCON trial, a nontargeted agent trial that looked at fulvestrant versus anastrozole in the first-line setting in patients who never had any hormone therapy before. So, the FALCON trial has a very unique population, but MONARCH-2 is closer to that population than it is to the population in PALOMA-3.

So, patients actually had a very good progression-free survival receiving fulvestrant and placebo, but it was markedly increased longer than we’ve seen in any of the trials with fulvestrant with the addition of abemaciclib, again because you started out with a very hormone sensitive group of patients or their tumors were very hormone sensitive. And the hazard ratios and the degree of benefit are similar to what we saw in PALOMA-3. It’s just the numbers are longer. It’s interesting, actually. It told us not only that abemaciclib was highly effective in this setting, as we expected, but also that if you used hormone therapy without giving chemotherapy beforehand, you can actually keep people on hormone therapy for a long time. So, I think that it actually supports the way many of us have treated our patients, which is that if you have cancer that’s progressing on an aromatase inhibitor in the adjuvant setting or shortly thereafter, using fulvestrant combined with the CDK4/6 inhibitor is a great approach. You don’t need to give those patients chemotherapy because you can potentially keep them on therapy for a median of 2 years. It’s really quite amazing.

The other thing we learned from MONARCH-2 is about the toxicity of abemaciclib. They started out using the same dose that we used in the single-agent MONARCH-1 trial, but patients had a lot of grade 3 diarrhea more than was really acceptable in this patient population. So, we reduced the dose shortly after, after only a small number of patients had been randomized, and with that reduced dose, the degree of grade 3 diarrhea reduced down to about 11%. That actually seems to be much more acceptable, but it is true that in patients receiving abemaciclib, you have to warn them about diarrhea, just like we tell patients about their count checks and all of that. It should be on the patient information that all patients receive before they take that first pill, because they need to have Imodium or loperamide or some other antidiarrheal agent with them.

Unlike the drug neratinib recently approved, they didn’t need to take the antidiarrheal therapy before they even start, but they’ve got to have it with them because some patients will have grade 3 diarrhea. We know that to be the case, and so you need to take medication as soon as you start having loose stools so you don’t get into a bad situation. And we often will check in with patients after the first few days just to make sure they’re doing well.

Transcript Edited for Clarity