Hope S. Rugo, MD: So, at the European Society of Medical Oncology meeting this year in Madrid, Spain, we saw the exciting data from MONARCH 3. The MONARCH trials numbered themselves backwards—MONARCH 2 was second-line therapy and MONARCH 3 is first-line therapy, but that just has to do with which trial started first. But now this is the second to last trial in the metastatic setting. We’re still waiting on the ribociclib second-line data in the MONALEESA trial series, but this is our second to last trial showing that cyclin-dependent kinase 4/6 inhibitors are here to stay, and they work really well in our patients with hormone receptor-positive advanced breast cancer. So, exciting data.

MONARCH 3 was designed in a similar way to PALOMA-2, actually more than MONALEESA. MONALEESA was a 1:1, PALOMA 2:1, and MONARCH 3 is a 2:1 randomization of just under 500 patients. So, 493 patients, who have not received any treatment for metastatic hormone receptor-positive breast cancer, were randomized to receive a nonsteroidal aromatase inhibitor plus either abemaciclib or a placebo. Now the nonsteroidal aromatase inhibitor was different from the other 2 trials in that you could choose letrozole or anastrozole. I thought that was a very clever and a reasonable thing to do because we don’t know that it makes any difference at all.

And the patients who were enrolled were also similar to what we’ve seen across the board in the first-line studies with palbociclib and ribociclib. So, a little more than 50% of the patients had visceral disease, which is so interesting. We would have thought it would have been a lot lower in these ER-positive untreated metastatic patients.

Prior chemotherapy, which was given in the neoadjuvant or adjuvant setting, was seen in just the 35% to 40% group. Again, very similar to what you would expect. And then there are the patients who had had no prior endocrine therapy. Some of those patients will be patients who have de novo metastatic hormone receptor-positive disease, but not all of them because some of them may just have not taken their adjuvant endocrine therapy. That was between 52% to 54%. So, that’s actually a fairly high number. And more similar to what we saw in PALOMA-1, the phase II trial that led to the accelerated approval of palbociclib, just a little over 50% of patients had no prior endocrine exposure.

So, what did they see? We know it was a positive trial from the press release. What they saw was a marked improvement in progression-free survival, the primary endpoint in patients receiving abemaciclib versus those receiving their placebo. And the progression-free survival is 14.7 months versus not yet reached. We know that it will be out there at least as good as the other 2 trials that have reported a progression-free survival for the experimental arm, PALOMA-2 and MONALEESA-2, but we don’t know exactly what that number is. I expect we’ll have it in the next 6 to 12 months or so. The hazard ratio was 0.543, so very, very good and exactly what we would expect, and this was highly statistically significant. So, really good data. The other things that they actually looked at that were a little bit different from what we’ve seen in some of the other trials was they made a big attempt, the investigators, to try and evaluate whether there were subgroups of patients who benefited more or less.

Now everybody’s done that in their trials. But they actually wanted to know who does worse overall, regardless of treatment, even though you benefit. So, the forest plot looks superimposable with the other agents. There was a benefit across the board regardless of the subset that you looked at. But one of the things that they looked at was treatment-free interval, and they picked 3 years. They found that patients who had a treatment-free interval from adjuvant therapy, to start a metastatic treatment of less than 36 months, had actually a 9-month progression-free survival in the control arm, so substantially shorter than in the trial population at large versus not reached in the abemaciclib arm. Dramatically better in the abemaciclib arm, which is important because that’s a group of patients we think of as being a little more resistant to hormone therapy because they have a short progression-free survival with their first-line endocrine therapy.

And then they looked at the patients who had a treatment-free interval of 36 months or longer, and actually that group was not reached on either end. So, we don’t know what’s going to happen in that group. Patients who were way, way far out actually may take a longer time to see a separation with the benefit of cyclin-independent kinase inhibitors. And then they looked at the usual suspects—liver, visceral, bone, and bone-only. Not bone-only and patients with bone-only disease do better, we know that already. Few patients with visceral disease do a little worse. But they all benefitted from abemaciclib. So, one of the thoughts that has come out of that is that maybe we could take the group of patients who still benefit but do a little worse overall, and add additional agents. That may be a place where we’ll look at immunotherapy, for example.

One of the issues that has come up between abemaciclib and the other 2 agents is that abemaciclib is a little more different than the other 2. It can be dosed continuously because it doesn’t have as much neutropenia as the other 2 agents and it has a lot more diarrhea than the other 2 agents. All of them cause all those side effects, it’s just relative degree. So, they only saw a 21% rate of grade 3/4 diarrhea, which is actually substantially one-third of what has been seen with palbociclib and ribociclib. And the drug is given continuously rather than 3 weeks on, 1 week off. It’s definitely much less bone marrow suppressive. Diarrhea, however, was increased so they had a 9.5% rate of grade 3 diarrhea and a 27% rate of grade 2 diarrhea—grade 2 diarrhea being bothersome to patients. Now this can be easily controlled with the use of antidiarrheal therapy, but it is a real consideration for patients who might have an issue already with their GI track and diarrhea. On the other hand, if you have patients who have bone marrow infiltration or had a lot of radiation, this drug is going to be much better tolerated in terms of bone marrow tolerance. Obviously, there are no survival data, it’s still too early, but it’s just yet another feather in the cap of the cyclin-dependent kinase inhibitors.

Now we’re going to have a wealth of riches similar to what we had. We were talking about how it’s similar to aromatase inhibitors. We had the nonsteroidals and then we had exemestane as the steroidal. We have the 2—palbociclib, ribociclib—they’re similar, and abemaciclib, which is a little more different. The other thing about abemaciclib that is unique is that in the MONARCH-1 trial, we showed that the response rate—in patients who were reasonably heavily pretreated, no prior CDK4/6 drugs, to single-agent abemaciclib—was just under 20%: 19.7%. And in some cases, this was quite durable. So, we know it acts effectively as a single agent. There are a little data on palbociclib suggesting it has a lower but some efficacy as a single agent.

The question is, can we give these drugs in sequence, and how do we decide? Other than what I just suggested, the patient who has GI problems, you wouldn’t give her abemaciclib. The patient who has low counts, problems with count tolerance, you’d probably give abemaciclib over and above the other 2 agents. But then how else do we decide on this? What’s the right hormone therapy partner? We just don’t know yet. My suspicion is that we’re going to be giving palbociclib and/or ribociclib in the first-line setting because they came out first. And that was what we saw from the aromatase inhibitors. It lasted until they went off patent really.

So, we’re going to give those drugs first. And when patients progress, we’re going to consider a trial of abemaciclib either in combination or on its own as a way to look at a slightly different agent for effectiveness. But abemaciclib crosses the blood brain barrier. Maybe we’ll be giving it first-line more frequently than I’m thinking about now.

MONARCH 3 is the third of the 3 cyclin-independent inhibitors trials to report data in the first-line setting. Data are excellent, look fabulous, and further convince you, if you weren’t convinced already, that CDK4/6 inhibitors are here to stay and are helping our patients tremendously. What we’re looking forward to now is the adjuvant setting. We have some exciting data in the neoadjuvant setting showing that we can cause complete cell cycle suppression very rapidly. Now we’ll see if we can actually cure more women with hormone receptor-positive breast cancer, both from early and late relapses. It’s going to be a fascinating time to look at those data in the over 15,000 women who will be enrolled in adjuvant CDK4/6 inhibitor trials in the next short while.

Transcript Edited for Clarity